rs371552806
Variant summary
Our verdict is Uncertain significance. Variant got 0 ACMG points: 0P and 0B.
This summary comes from the ClinGen Evidence Repository: The c.4210G>A (p.Val1404Met) variant in MYH7 has been identified in 3 individuals with HCM (Wang 2014 PMID:25132132; Invitae pers. comm.) and also segregated in 1 affected relative with HCM (Invitae pers. comm.); however this data is currently insufficient to apply PP1. Of note, 1 of the 2 affected individuals from Invitae also carried a splice variant in MYBPC3 and was in their mid 20s at the time of testing. This variant was identified in 0.004% (FAF 95% CI; 9/129152) of European chromosomes by gnomAD v2.1.1 (http://gnomad.broadinstitute.org). Since the MYH7 specifications state that PS4 is only applicable if the variant is absent or rare in large population studies, the PS4 criterion was not applied (Kelly 2018 PMID:29300372). Computational prediction tools and conservation analysis were mixed about the potential impact of this variant. In summary, due to insufficient evidence, this variant meets criteria to be classified as uncertain significance for hypertrophic cardiomyopathy in an autosomal dominant manner. MYH7-specific ACMG/AMP criteria applied (Kelly 2018 PMID:29300372): none. LINK:https://erepo.genome.network/evrepo/ui/classification/CA014652/MONDO:0005045/002
Frequency
Consequence
NM_000257.4 missense
Scores
Clinical Significance
Conservation
Genome browser will be placed here
ACMG classification
Verdict is Uncertain_significance. Variant got 0 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
MYH7 | NM_000257.4 | c.4210G>A | p.Val1404Met | missense_variant | 31/40 | ENST00000355349.4 | |
MYH7 | NM_001407004.1 | c.4210G>A | p.Val1404Met | missense_variant | 30/39 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
MYH7 | ENST00000355349.4 | c.4210G>A | p.Val1404Met | missense_variant | 31/40 | 1 | NM_000257.4 | P1 |
Frequencies
GnomAD3 genomes AF: 0.0000526 AC: 8AN: 152234Hom.: 0 Cov.: 33
GnomAD3 exomes AF: 0.0000278 AC: 7AN: 251426Hom.: 0 AF XY: 0.0000294 AC XY: 4AN XY: 135892
GnomAD4 exome AF: 0.0000630 AC: 92AN: 1460698Hom.: 0 Cov.: 34 AF XY: 0.0000674 AC XY: 49AN XY: 726660
GnomAD4 genome AF: 0.0000526 AC: 8AN: 152234Hom.: 0 Cov.: 33 AF XY: 0.0000269 AC XY: 2AN XY: 74374
ClinVar
Submissions by phenotype
not provided Uncertain:5
Uncertain significance, no assertion criteria provided | clinical testing | Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center | - | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Feb 24, 2023 | Reported in association with HCM and DCM in published literature (Wang et al., 2014; van Lint et al., 2019; Verdonschot et al., 2020); In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 24215330, 34542152, 35653365, 30847666, 32880476, 25132132) - |
Uncertain significance, criteria provided, single submitter | clinical testing | AiLife Diagnostics, AiLife Diagnostics | Jun 29, 2021 | - - |
Uncertain significance, no assertion criteria provided | clinical testing | Clinical Genetics, Academic Medical Center | - | - - |
Uncertain significance, no assertion criteria provided | clinical testing | Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+ | - | - - |
Cardiomyopathy Uncertain:3
Uncertain significance, criteria provided, single submitter | clinical testing | Color Diagnostics, LLC DBA Color Health | Mar 23, 2023 | This missense variant replaces valine with methionine at codon 1404 of the MYH7 protein. Computational prediction suggests that this variant may have a deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in an individual affected with hypertrophic cardiomyopathy (PMID: 25132132) and in an individual affected with dilated cardiomyopathy (PMID: 32880476). This variant has been identified in 10/282824 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. - |
Uncertain significance, criteria provided, single submitter | clinical testing | CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario | Mar 29, 2023 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | All of Us Research Program, National Institutes of Health | Feb 05, 2024 | This missense variant replaces valine with methionine at codon 1404 of the MYH7 protein. Computational prediction suggests that this variant may have a deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in an individual affected with hypertrophic cardiomyopathy (PMID: 25132132) and in an individual affected with dilated cardiomyopathy (PMID: 32880476). This variant has been identified in 10/282824 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. - |
Hypertrophic cardiomyopathy Uncertain:2
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Sep 27, 2022 | This sequence change replaces valine, which is neutral and non-polar, with methionine, which is neutral and non-polar, at codon 1404 of the MYH7 protein (p.Val1404Met). This variant is present in population databases (rs371552806, gnomAD 0.006%). This missense change has been observed in individual(s) with dilated cardiomyopathy and/or hypertrophic cardiomyopathy (PMID: 25132132, 32880476). ClinVar contains an entry for this variant (Variation ID: 42999). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt MYH7 protein function. 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 | The c.4210G>A (p.Val1404Met) variant in MYH7 has been identified in 3 individuals with HCM (Wang 2014 PMID:25132132; Invitae pers. comm.) and also segregated in 1 affected relative with HCM (Invitae pers. comm.); however this data is currently insufficient to apply PP1. Of note, 1 of the 2 affected individuals from Invitae also carried a splice variant in MYBPC3 and was in their mid 20s at the time of testing. This variant was identified in 0.004% (FAF 95% CI; 9/129152) of European chromosomes by gnomAD v2.1.1 (http://gnomad.broadinstitute.org). Since the MYH7 specifications state that PS4 is only applicable if the variant is absent or rare in large population studies, the PS4 criterion was not applied (Kelly 2018 PMID:29300372). Computational prediction tools and conservation analysis were mixed about the potential impact of this variant. In summary, due to insufficient evidence, this variant meets criteria to be classified as uncertain significance for hypertrophic cardiomyopathy in an autosomal dominant manner. MYH7-specific ACMG/AMP criteria applied (Kelly 2018 PMID:29300372): none. - |
Dilated cardiomyopathy 1S Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Neuberg Centre For Genomic Medicine, NCGM | - | The observed missense c.4210G>A(p.Val1404Met) variant in MYH7 gene has been reported previously in individuals affected with cardiomyopathy (Verdonschot JAJ, et al., 2020; Wang J, et al., 2014). The p.Val1404Met variant has been reported with allele frequency of 0.003% in gnomAD Exomes. This variant has been submitted to the ClinVar database as Uncertain Significance (multiple submissions). The amino acid change p.Val1404Met in MYH7 is predicted as conserved by GERP++ and PhyloP across 100 vertebrates. The amino acid Val at position 1404 is changed to a Met changing protein sequence and it might alter its composition and physico-chemical properties. However, additional functional studies will be required to prove the pathogenicity of this variant. For these reasons, this variant has been classified as a Variant of Uncertain Significance (VUS). - |
Primary dilated cardiomyopathy Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Apr 05, 2019 | The p.Val1404Met variant in MYH7 has been reported in 1 individual with HCM (Wang 2014), and one with an unspecified mitochondrial disorder, but was also seen in this individual's unaffected father (DaRe 2013). In addition, it has been identified by our laboratory in 1 Caucasian individual with DCM. This variant has been identified in 2/66696 MYH7 chromosomes by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.org; dbSNP rs371552806). Clinvar: VUS (GeneDx, Invitae). Computational prediction tools and conservation analysis suggest that the p.Val1404Met variant may impact the protein, though this information is not predictive enough to determine pathogenicity. In summary, the clinical significance of the p.Val1404Met variant is uncertain. - |
Cardiovascular phenotype Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Feb 10, 2021 | The c.4210G>A (p.V1404M) alteration is located in exon 31 (coding exon 29) of the MYH7 gene. This alteration results from a G to A substitution at nucleotide position 4210, causing the valine (V) at amino acid position 1404 to be replaced by a methionine (M). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. - |
Hypertrophic cardiomyopathy 1 Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Genetics and Molecular Pathology, SA Pathology | Jul 21, 2021 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at