rs397516187
Variant summary
Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PS4_ModeratePP1_ModeratePM2PP3
This summary comes from the ClinGen Evidence Repository: The NM_000257.4(MYH7):c.3578G>A (p.Arg1193His) variant has been identified in at least 9 individuals with DCM, including 1 individual with an additional variant in another gene that may contribute to their disease and 1 individual with DCM and a bicuspid aortic valve (PS4_Moderate; GeneDx pers. comm.; LMM pers. comm.; OMGL pers. comm.). This variant also segregated in 5 affected relatives with DCM from 4 families (PP1_Moderate; LMM pers. comm.; OMGL pers. comm.). Additionally, this variant has also been reported in 1 individual with LVNC, 1 individual with non-ischemic cardiomyopathy and 1 individual with biventricular dilation with ventricular tachycardia (GeneDx pers. comm., Invitae pers. comm., LMM pers. comm.). This variant was absent from large population studies (PM2; gnomAD v2.1.1, http://gnomad.broadinstitute.org). Computational prediction tools and conservation analysis suggest that this variant may impact the protein (PP3). In summary, this variant meets criteria to be classified as likely pathogenic for dilated cardiomyopathy in an autosomal dominant manner. ACMG/AMP Criteria applied: PS4_Moderate, PP1_Moderate, PM2, PP3. LINK:https://erepo.genome.network/evrepo/ui/classification/CA013815/MONDO:0005021/002
Frequency
Consequence
NM_000257.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_pathogenic. Variant got 7 ACMG points.
Transcripts
RefSeq
Ensembl
Frequencies
GnomAD3 genomes Cov.: 31
GnomAD3 exomes AF: 0.00000844 AC: 2AN: 236944Hom.: 0 AF XY: 0.00 AC XY: 0AN XY: 129232
GnomAD4 exome AF: 0.00000484 AC: 7AN: 1447154Hom.: 0 Cov.: 34 AF XY: 0.00000139 AC XY: 1AN XY: 718534
GnomAD4 genome Cov.: 31
ClinVar
Submissions by phenotype
Hypertrophic cardiomyopathy Pathogenic:2
Likely pathogenic, reviewed by expert panel | curation | ClinGen Cardiomyopathy Variant Curation Expert Panel | Dec 22, 2021 | The NM_000257.4(MYH7):c.3578G>A (p.Arg1193His) variant has been identified in at least 9 individuals with DCM, including 1 individual with an additional variant in another gene that may contribute to their disease and 1 individual with DCM and a bicuspid aortic valve (PS4_Moderate; GeneDx pers. comm.; LMM pers. comm.; OMGL pers. comm.). This variant also segregated in 5 affected relatives with DCM from 4 families (PP1_Moderate; LMM pers. comm.; OMGL pers. comm.). Additionally, this variant has also been reported in 1 individual with LVNC, 1 individual with non-ischemic cardiomyopathy and 1 individual with biventricular dilation with ventricular tachycardia (GeneDx pers. comm., Invitae pers. comm., LMM pers. comm.). This variant was absent from large population studies (PM2; gnomAD v2.1.1, http://gnomad.broadinstitute.org). Computational prediction tools and conservation analysis suggest that this variant may impact the protein (PP3). In summary, this variant meets criteria to be classified as likely pathogenic for dilated cardiomyopathy in an autosomal dominant manner. ACMG/AMP Criteria applied: PS4_Moderate, PP1_Moderate, PM2, PP3. - |
Pathogenic, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Nov 30, 2024 | This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 1193 of the MYH7 protein (p.Arg1193His). This variant is present in population databases (rs397516187, gnomAD 0.001%). This missense change has been observed in individuals with clinical features of dilated cardiomyopathy or hypertrophic cardiomyopathy (PMID: 22464770, 27532257; external communication, internal data). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 42965). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is expected to disrupt MYH7 protein function with a positive predictive value of 95%. This variant disrupts the p.Arg1193 amino acid residue in MYH7. Other variant(s) that disrupt this residue have been observed in individuals with MYH7-related conditions (PMID: 15769782), which suggests that this may be a clinically significant amino acid residue. For these reasons, this variant has been classified as Pathogenic. - |
not provided Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Sep 03, 2024 | Observed in multiple unrelated patients with cardiomyopathy referred for genetic testing at GeneDx and in published literature; DCM is most common but LVNC and HCM have also been reported (PMID: 22464770, 27532257, 37652022); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 29300372, 22464770, 27532257, 37652022) - |
Primary familial dilated cardiomyopathy Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute | Jul 24, 2017 | - - |
Primary dilated cardiomyopathy Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | All of Us Research Program, National Institutes of Health | Mar 24, 2024 | This missense variant replaces arginine with histidine at codon 1193 in the neck and hinge domain of the MYH7 protein. Computational prediction tools indicate that this variant has a deleterious impact on protein structure and function. To our knowledge, functional studies have not been reported for this variant. This variant has been reported in at least nine individuals affected with dilated cardiomyopathy (PMID: 22464770, 27532257, 29300372, 36007715; ClinVar SCV000564445.5). It has been shown that this variant segregates with disease in multiple affected individuals across multiple families (PMID: 29300372; ClinVar SCV000564445.5). This variant has been identified in 2/236944 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Likely Pathogenic. - |
Primary familial hypertrophic cardiomyopathy Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Dec 07, 2023 | Variant summary: MYH7 c.3578G>A (p.Arg1193His) results in a non-conservative amino acid change located in the Myosin tail domain (IPR002928) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 8.4e-06 in 236944 control chromosomes (gnomAD). c.3578G>A has been reported in the literature in individuals affected with Hypertrophic Cardiomyopathy or Dilated Cardiomyopathy (Lakdawala_2012, Pugh_2014, Walsh_2017). These data indicate that the variant is likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 22464770, 24503780, 27532257, 29300372). Five submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. One submitter classified it as pathogenic, two (including a ClinGen expert panel) classified it as likely pathogenic, and two classified it as uncertain significance. Based on the evidence outlined above, the variant was classified as likely pathogenic. - |
Cardiovascular phenotype Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Ambry Genetics | May 20, 2024 | The c.3578G>A (p.R1193H) alteration is located in exon 27 (coding exon 25) of the MYH7 gene. This alteration results from a G to A substitution at nucleotide position 3578, causing the arginine (R) at amino acid position 1193 to be replaced by a histidine (H). Based on data from gnomAD, the A allele has an overall frequency of 0.001% (2/236944) total alleles studied. This alteration has been reported in subjects with hypertrophic cardiomyopathy (HCM) and dilated cardiomyopathy (DCM) (Walsh, 2017; Lakdawala, 2012; Kelly, 2018; external communication). This amino acid position is highly conserved in available vertebrate species. This alteration is predicted to be deleterious by in silico analysis. Based on the available evidence, this alteration is classified as likely pathogenic. - |
not specified Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Feb 01, 2021 | Variant classified as Uncertain Significance - Favor Pathogenic. The p.Arg1193His variant in MYH7 has been identified in 7 Caucasian individuals with DCM and segregated with disease in 4 affected relatives, including one obligate carrier, and has been reported in one individual with HCM (Lakdawala 2012 PMID: 22464770, Walsh 2017 PMID: 27532257, LMM data). It has also been identified in 0.01% (1/104518) of European chromosomes by gnomAD (http://gnomad.broadinstitute.org). Computational prediction tools and conservation analyses suggest that this variant may impact the protein, though this information is not predictive enough to determine pathogenicity. A different variant (p.Arg1193Ser) at this position has been reported in 1 individual with DCM and segregated with disease in 3 affected family members (Villard 2005 PMID: 15769782), supporting that a change at this position may not be tolerated. In summary, while there is some suspicion for a pathogenic role, the clinical significance of this variant is uncertain. ACMG/AMP Criteria applied: PS4_Moderate, PM2_Supporting, PP1, PP3. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at