rs121913646
Variant summary
Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PS4_SupportingPM2
This summary comes from the ClinGen Evidence Repository: TThe c.1925C>T (p.Ser642Leu) variant in MYH7 has been identified in 4 individuals with DCM (PS4_Supporting; Daehmlow 2002 PMID:12379228; OMGL pers. comm., Invitae pers. comm., Ambry pers. comm.). This variant was absent from large population studies (PM2; http://gnomad.broadinstitute.org). This variant lies in the head region of the protein (aa 181-937) and missense variants in this region are statistically more likely to be disease-associated (PM1; Walsh 2017 PMID:27532257). Computational prediction tools and conservation analysis do not provide strong support for or against an impact to the protein. In summary, due to lack of sufficient evidence, this variant meets criteria to be classified as uncertain significance for dilated cardiomyopathy in an autosomal dominant manner. MYH7-specific ACMG/AMP criteria applied (Kelly 2018 PMID:29300372): PM2; PS4_Supporting LINK:https://erepo.genome.network/evrepo/ui/classification/CA011471/MONDO:0005045/002
Frequency
Consequence
ENST00000355349.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Uncertain_significance. Variant got 3 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
MYH7 | NM_000257.4 | c.1925C>T | p.Ser642Leu | missense_variant | 17/40 | ENST00000355349.4 | NP_000248.2 | |
MYH7 | NM_001407004.1 | c.1925C>T | p.Ser642Leu | missense_variant | 16/39 | NP_001393933.1 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
MYH7 | ENST00000355349.4 | c.1925C>T | p.Ser642Leu | missense_variant | 17/40 | 1 | NM_000257.4 | ENSP00000347507 | P1 |
Frequencies
GnomAD3 genomes Cov.: 32
GnomAD4 exome AF: 0.00000274 AC: 4AN: 1461838Hom.: 0 Cov.: 33 AF XY: 0.00000138 AC XY: 1AN XY: 727206
GnomAD4 genome Cov.: 32
ClinVar
Submissions by phenotype
Hypertrophic cardiomyopathy Uncertain:2
Uncertain significance, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Dec 22, 2018 | Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. This variant has been observed in an individual affected with dilated cardiomyopathy (PMID: 12379228). ClinVar contains an entry for this variant (Variation ID: 14113). This variant is not present in population databases (ExAC no frequency). This sequence change replaces serine with leucine at codon 642 of the MYH7 protein (p.Ser642Leu). The serine residue is highly conserved and there is a large physicochemical difference between serine and leucine. This variant is found within a region of MYH7 between codons 181 and 937 that contains the majority of the myosin head domain. Missense variants in this region have been shown to be significantly overrepresented in individuals with hypertrophic cardiomyopathy (PMID: 27532257). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. - |
Uncertain significance, reviewed by expert panel | curation | ClinGen Cardiomyopathy Variant Curation Expert Panel | Jun 16, 2021 | TThe c.1925C>T (p.Ser642Leu) variant in MYH7 has been identified in 4 individuals with DCM (PS4_Supporting; Daehmlow 2002 PMID:12379228; OMGL pers. comm., Invitae pers. comm., Ambry pers. comm.). This variant was absent from large population studies (PM2; http://gnomad.broadinstitute.org). This variant lies in the head region of the protein (aa 181-937) and missense variants in this region are statistically more likely to be disease-associated (PM1; Walsh 2017 PMID:27532257). Computational prediction tools and conservation analysis do not provide strong support for or against an impact to the protein. In summary, due to lack of sufficient evidence, this variant meets criteria to be classified as uncertain significance for dilated cardiomyopathy in an autosomal dominant manner. MYH7-specific ACMG/AMP criteria applied (Kelly 2018 PMID:29300372): PM2; PS4_Supporting - |
Dilated cardiomyopathy 1S Pathogenic:1
Pathogenic, no assertion criteria provided | literature only | OMIM | Oct 18, 2002 | - - |
Cardiovascular phenotype Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Mar 31, 2020 | The p.S642L variant (also known as c.1925C>T), located in coding exon 15 of the MYH7 gene, results from a C to T substitution at nucleotide position 1925. The serine at codon 642 is replaced by leucine, an amino acid with dissimilar properties, and is located in the myosin head domain. This variant was detected in an individual with dilated cardiomyopathy (Daehmlow S et al. Biochem. Biophys. Res. Commun., 2002 Oct;298:116-20). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. - |
Hypertrophic cardiomyopathy 1 Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen | Aug 04, 2023 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at