| Date | Panel | Item | Activity | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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| Cardiac conduction disease v0.33 | TRPM4 | Bryony Thompson Marked gene: TRPM4 as ready | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Cardiac conduction disease v0.33 | TRPM4 | Bryony Thompson Gene: trpm4 has been classified as Amber List (Moderate Evidence). | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Cardiac conduction disease v0.33 | TRPM4 | Bryony Thompson Classified gene: TRPM4 as Amber List (moderate evidence) | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Cardiac conduction disease v0.33 | TRPM4 | Bryony Thompson Gene: trpm4 has been classified as Amber List (Moderate Evidence). | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Cardiac conduction disease v0.32 | TRPM4 |
Bryony Thompson gene: TRPM4 was added gene: TRPM4 was added to Cardiac conduction disease. Sources: NHS GMS Mode of inheritance for gene: TRPM4 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted Publications for gene: TRPM4 were set to 19726882; 26820365; 21887725; 32681584; 20562447; 25531103; 27207958; 29568272; 29748318; 36352534; 35205305 Phenotypes for gene: TRPM4 were set to progressive familial heart block type IB MONDO:0011474 Mode of pathogenicity for gene: TRPM4 was set to Other Review for gene: TRPM4 was set to AMBER Added comment: A lot of the originally reported variants are more common in gnomAD than is expected for a dominant condition. However, there are at least 2 families that have decent segregation evidence and that suggest gain of function is the mechanism of disease. Loss of function variants are common in gnomAD. Publications that contribute to gene-disease association: PMID: 19726882 - linkage analysis in a large South African Afrikaner family with progressive familial heart block identified linkage to chromosomal locus 19q13.3. p.E7K was found to segregate with PFHB in the family. The variant was found to lead to a gain of function. The variant is rare in gnomAD v4 - 2 hets. PMID: 26820365 - identified 13 “rare” TRPM4 variants in 95 unrelated patients with progressive cardiac conduction disease (PCCD). Some of the variants are a bit too common in gnomAD to be associated with dominant disease. One of the variants (p.Ile376Thr - 3 hets in gnomAD v4) segregated with PCCD in a large French 4-generation pedigree. TRPM4-p.I376T results in an increased current density in patch-clamp assays & augmented TRPM4 channel expression at the cell surface. PMID: 21887725 - 8 “rare” TRPM4 variants identified in 160 cases with cardiac conduction disturbances. 3 of the variants had some supporting segregation evidence (Y790H - 3 segs, P970S - 1 seg, K914R - 1 seg) PMID: 32681584 - in vitro functional assays on K914R which demonstrate a gain of function Publications with uncertainty: PMID: 20562447 - 3 families with dominant isolated cardiac conduction blocks were used for linkage analysis and a genomic interval on the long arm of chromosome 19 in an interval of ~300 genes. Screened 12 genes. TRPM4 p.Ala432Thr (L1 family), p.Arg164Trp (F1 family), p.Gly844Asp (F2 family). Ala432Thr and Gly844Asp are too common in gnomAD for a Mendelian AD disease (see below). Incomplete penetrance for p.Arg164Trp in family F1. All 3 variants increased current density in patch-clamp assays compared to WT (p<0.05). PMID: 25531103 - null mouse model has cardiac hypertrophy and electrophysiological alterations PMID: 27207958 - “rare” missense variants identified in children with atrioventricular block. Asp198Gly (2 hets in gnomAD v4), Ala432Thr/Gly582Ser present in 2 families (A432T - 558 alleles, 5 homs; G582S - 604 alleles, 7 homs in gnomAD v4) and also carried variants in SCN5 & NKX2.5, Thr677Ile (1 het in gnomAD v4), Val921Ile (101 alleles, 1 hom in gnomAD v4). Ala432Thr/Gly582Ser demonstrated loss of function in patch clamp assay - A432T alone was LoF, while G582S alone was GoF. D198G, T677I, and V921I didn’t alter function in the assays PMID: 29568272 - p.A101T (3299 alleles, 51 homs), p.Q854R (1610 alleles, 5 homs), p.S1044C (7 hets), p.A101T/P1204L (5013 alleles, 11 homs). In patch-clamp assays, all variants reduced current except Q854R which increased the current (GoF) PMID: 29748318 - synonymous variant c.858G>A shown to lead to exon 7 skipping, expected to cause loss of function identified in 2 siblings with cardiac conduction defects. It was inherited from apparently unaffected mother PMID: 36352534, 35205305 - both report TRPM4 c.2351G>A, p.Gly844Asp in association with conduction disease. However, the variant is highly prevalent in gnomAD v4 (2200 alleles, 1 homozygote) Sources: NHS GMS |
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