Intellectual disability syndromic and non-syndromic
Gene: LRP1 Amber List (moderate evidence)I don't know
PMID: 42649465 – 15 individuals with neurodevelopmental disability with heterozygous LRP1 variants, including 6 predicted LoF variants, 7 missense variants and 2 indels. 10 variants occurred de novo, 3 individuals from 2 families had inherited the variant from an affected father, 2 with unknown inheritance. All patients had multisystemic involvement including developmental delay/intellectual disability, behavioural concerns, Autism, ADHD, congenital heart disease (supravalvular pulmonary stenosis, pulmonary stenosis, pulmonary atresia, PDA, VSD, ASD, interrupted aortic arch) and craniofacial anomalies. No functional testing performed, however haploinsufficiency proposed to be mechanism of disease due to overlapping clinical features of patients with predicted LoF variants and missense variants.
PMID: 40374006 - a single proband with refractory epilepsy with compound heterozygous variants in LRP1:p.(Gly2546Ser);p.(Val3412Ile), plus additional variants in OPHN1 and UBR4. LRP1:p.Gly2546Ser homs present in gnomAD v4. Monogenic and polygenic (LRP1+/- OPHN +/- UBR4) knockdown flies showed increases in seizure rate, though no variant specific residue testing was performed.
PMID: 36307211 – two siblings with prenatally detected congenital anomalies of ascites, polyhydramnios and cerebral ventriculomegaly, and postnatal features of respiratory distress, corneal opacities, dysmorphic facial features, ascites, hypotonia, ventriculomegaly, and congenital heart disease (including PDA and aortic coarctation). Both sibs compound heterozygous for variants in LRP1: [c.11420G>C, p.(Cys3807Ser)];[ c.12407T>G, p.(Val4136Gly)]. Mouse knockout studies show congenital heart defects, altered bone and facial development.
PMID: 36067312 – nine individuals reported with developmental dysplasia of the hip, two with a likely AD inheritance pattern, with heterozygous missense and splicing variants in LRP1. A mouse heterozygous knock in model using a patient variant (R1783W) and an LRP1 knockout model recapitulated the DDH phenotype.
PMID: 33776059 - two unrelated probands with early onset macular drusen with compound heterozygous LRP1 variants. Family M54: [c.650 C>T, p.(Ala217Val)]; [c.9628G>C, p.(Glu3210Gln)]. Family M70, [c.2910 G> A, p.(Ser970=)];[c.11930 C>T, p.(Glu3210Gln)]. Homs present in gnomAD for p.(Ala217Val), p.(Ser970=). No functional data presented.
PMID: 26142438 – large consanguineous Pakistani family with homozygous LRP1:c.3734A>G, p.(Lys1245Arg) variants and a keratosis pilaris atrophicans phenotype. Normal development, growth and no additional reported health outcomes. Patient fibroblast qRT-PCR showed reduced mRNA expression and protein levels.Created: 16 Sep 2026, 10:23 a.m. | Last Modified: 16 Sep 2026, 10:23 a.m.
Panel Version: 2.612
Mode of inheritance
BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Phenotypes
Neurodevelopmental disorder, MONDO:0700092; Syndromic disease, MONDO:0002254; developmental dysplasia of the hip 3, MONDO:0958037; keratosis pilaris atrophicans, MONDO:0018855; ?Keratosis pilaris atrophicans, MIM#604093; Developmental dysplasia of the hip 3, MIM#620690
Publications
I don't know
PMID 36067312: third gene-disease association proposed with DDH. Two parent-child pairs identified with missense variants in this gene. GnomadV4: one is present in over 45 individuals and the other in over 25. Other rare variants identified in additional individuals as part of a cohort study, with little supportive information. Functional studies on the original two variants support LoF effect, and mouse model recapitulates phenotype. Overall, borderline Red-Amber.Created: 23 Aug 2024, 1:31 p.m.
Mode of inheritance
MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Phenotypes
Developmental dysplasia of the hip 3, MIM# 620690
Publications
Comment on list classification: Two papers without related phenotypes and little overall evidence for gene disease association.Created: 6 Sep 2021, 3:44 p.m.
I don't know
PMID: 26142438 - 1 hom missense segregated in 3 sibs and a homozygous 1st cousin with keratosis pilaris atrophicans. Variant is very rare in gnomAD. Patient fibroblast qRT-PCR shows significantly reduced mRNA expression and resulting protein expression
PMID: 33776059 - 2x unrelated chet missense patients with inherited retinal disorder/macular drusen (most missense rare, no functional).
GnomAD - no homozygous PTCsCreated: 6 Sep 2021, 3:35 p.m.
Mode of inheritance
BIALLELIC, autosomal or pseudoautosomal
Phenotypes
?Keratosis pilaris atrophicans MIM#604093
Publications
gene: LRP1 was added gene: LRP1 was added to Intellectual disability syndromic and non-syndromic. Sources: Expert Review Amber,Victorian Clinical Genetics Services Mode of inheritance for gene: LRP1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted Publications for gene: LRP1 were set to 26142438; 33776059; 36067312 Phenotypes for gene: LRP1 were set to Developmental dysplasia of the hip 3, MIM# 620690; Keratosis pilaris atrophicans MIM#604093
If promoting or demoting a gene, please provide comments to justify a decision to move it.
Genes included in a Genomics England gene panel for a rare disease category (green list) should fit the criteria A-E outlined below.
These guidelines were developed as a combination of the ClinGen DEFINITIVE evidence for a causal role of the gene in the disease(a), and the Developmental Disorder Genotype-Phenotype (DDG2P) CONFIRMED DD Gene evidence level(b) (please see the original references provided below for full details). These help provide a guideline for expert reviewers when assessing whether a gene should be on the green or the red list of a panel.
A. There are plausible disease-causing mutations(i) within, affecting or encompassing an interpretable functional region(ii) of this gene identified in multiple (>3) unrelated cases/families with the phenotype(iii).
OR
B. There are plausible disease-causing mutations(i) within, affecting or encompassing cis-regulatory elements convincingly affecting the expression of a single gene identified in multiple (>3) unrelated cases/families with the phenotype(iii).
OR
C. As definitions A or B but in 2 or 3 unrelated cases/families with the phenotype, with the addition of convincing bioinformatic or functional evidence of causation e.g. known inborn error of metabolism with mutation in orthologous gene which is known to have the relevant deficient enzymatic activity in other species; existence of an animal model which recapitulates the human phenotype.
AND
D. Evidence indicates that disease-causing mutations follow a Mendelian pattern of causation appropriate for reporting in a diagnostic setting(iv).
AND
E. No convincing evidence exists or has emerged that contradicts the role of the gene in the specified phenotype.
(i)Plausible disease-causing mutations: Recurrent de novo mutations convincingly affecting gene function. Rare, fully-penetrant mutations - relevant genotype never, or very rarely, seen in controls. (ii) Interpretable functional region: ORF in protein coding genes miRNA stem or loop. (iii) Phenotype: the rare disease category, as described in the eligibility statement. (iv) Intermediate penetrance genes should not be included.
It’s assumed that loss-of-function variants in this gene can cause the disease/phenotype unless an exception to this rule is known. We would like to collect information regarding exceptions. An example exception is the PCSK9 gene, where loss-of-function variants are not relevant for a hypercholesterolemia phenotype as they are associated with increased LDL-cholesterol uptake via LDLR (PMID: 25911073).
If a curated set of known-pathogenic variants is available for this gene-phenotype, please contact us at panelapp@genomicsengland.co.uk
We classify loss-of-function variants as those with the following Sequence Ontology (SO) terms:
Term descriptions can be found on the PanelApp homepage and Ensembl.
If you are submitting this evaluation on behalf of a clinical laboratory please indicate whether you report variants in this gene as part of your current diagnostic practice by checking the box
Standardised terms were used to represent the gene-disease mode of inheritance, and were mapped to commonly used terms from the different sources. Below each of the terms is described, along with the equivalent commonly-used terms.
A variant on one allele of this gene can cause the disease, and imprinting has not been implicated.
A variant on the paternally-inherited allele of this gene can cause the disease, if the alternate allele is imprinted (function muted).
A variant on the maternally-inherited allele of this gene can cause the disease, if the alternate allele is imprinted (function muted).
A variant on one allele of this gene can cause the disease. This is the default used for autosomal dominant mode of inheritance where no knowledge of the imprinting status of the gene required to cause the disease is known. Mapped to the following commonly used terms from different sources: autosomal dominant, dominant, AD, DOMINANT.
A variant on both alleles of this gene is required to cause the disease. Mapped to the following commonly used terms from different sources: autosomal recessive, recessive, AR, RECESSIVE.
The disease can be caused by a variant on one or both alleles of this gene. Mapped to the following commonly used terms from different sources: autosomal recessive or autosomal dominant, recessive or dominant, AR/AD, AD/AR, DOMINANT/RECESSIVE, RECESSIVE/DOMINANT.
A variant on one allele of this gene can cause the disease, however a variant on both alleles of this gene can result in a more severe form of the disease/phenotype.
A variant in this gene can cause the disease in males as they have one X-chromosome allele, whereas a variant on both X-chromosome alleles is required to cause the disease in females. Mapped to the following commonly used term from different sources: X-linked recessive.
A variant in this gene can cause the disease in males as they have one X-chromosome allele. A variant on one allele of this gene may also cause the disease in females, though the disease/phenotype may be less severe and may have a later-onset than is seen in males. X-linked inactivation and mosaicism in different tissues complicate whether a female presents with the disease, and can change over their lifetime. This term is the default setting used for X-linked genes, where it is not known definitately whether females require a variant on each allele of this gene in order to be affected. Mapped to the following commonly used terms from different sources: X-linked dominant, x-linked, X-LINKED, X-linked.
The gene is in the mitochondrial genome and variants within this can cause this disease, maternally inherited. Mapped to the following commonly used term from different sources: Mitochondrial.
Mapped to the following commonly used terms from different sources: Unknown, NA, information not provided.
For example, if the mode of inheritance is digenic, please indicate this in the comments and which other gene is involved.