ClinVar Miner

Submissions for variant NM_000257.4(MYH7):c.5422G>A (p.Gly1808Ser)

gnomAD frequency: 0.00002  dbSNP: rs369940645
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Total submissions: 9
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
ClinGen Cardiomyopathy Variant Curation Expert Panel RCV000456307 SCV001842659 uncertain significance Hypertrophic cardiomyopathy 2021-03-22 reviewed by expert panel curation The c.5422G>A (p.Gly1808Ser) variant in MYH7 has been reported in 3 individuals with HCM (Marsiglia 2013 PMID:24093860; Homburger 2016 PMID:27247418; Invitae pers. comm.), 1 individual with unspecified cardiomyopathy (Invitae pers. comm.) and in 1 individual with sudden cardiac death (Campuzano 2017 PMID:28255936). This variant has also been identified in 0.0045% (FAF 95% CI, 4/30616) of South Asian chromosomes in gnomAD v2.1.1 (https://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 do not provide strong support for or against an impact to the protein. In summary, due to a lack of sufficient 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.
Laboratory of Genetics and Molecular Cardiology, University of São Paulo RCV000201453 SCV000256137 likely pathogenic Hypertrophic cardiomyopathy 1 criteria provided, single submitter clinical testing
Invitae RCV000456307 SCV000546212 likely pathogenic Hypertrophic cardiomyopathy 2023-07-28 criteria provided, single submitter clinical testing In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. 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. ClinVar contains an entry for this variant (Variation ID: 217468). This missense change has been observed in individuals with dilated cardiomyopathy and/or hypertrophic cardiomyopathy (PMID: 19412328, 24093860, 27247418, 34542152; Invitae). This variant is present in population databases (rs369940645, gnomAD 0.01%). This sequence change replaces glycine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 1808 of the MYH7 protein (p.Gly1808Ser).
Equipe Genetique des Anomalies du Developpement, Université de Bourgogne RCV000201453 SCV000883092 likely pathogenic Hypertrophic cardiomyopathy 1 2018-11-21 criteria provided, single submitter clinical testing
Color Diagnostics, LLC DBA Color Health RCV001181802 SCV001347030 uncertain significance Cardiomyopathy 2023-02-21 criteria provided, single submitter clinical testing This missense variant replaces glycine with serine at codon 1808 of the MYH7 protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 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: 24093860) and in an individual affected with sudden death (PMID: 28255936). This variant has also been identified in 9/251466 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.
GeneDx RCV001762425 SCV002008875 uncertain significance not provided 2021-06-15 criteria provided, single submitter clinical testing Identified in patients with hypertrophic cardiomyopathy (HCM) and sudden cardiac death (SCD) in the published literature (Marsiglia et al., 2013; Homburger et al., 2016; Campuzano et al., 2017); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Reported in ClinVar but additional evidence is not available (ClinVar Variant ID#217468; Landrum et al., 2016); This variant is associated with the following publications: (PMID: 24093860, 27247418, 28255936, 31019283, 27535533)
Ambry Genetics RCV002345719 SCV002652890 uncertain significance Cardiovascular phenotype 2021-04-12 criteria provided, single submitter clinical testing The p.G1808S variant (also known as c.5422G>A), located in coding exon 35 of the MYH7 gene, results from a G to A substitution at nucleotide position 5422. The glycine at codon 1808 is replaced by serine, an amino acid with similar properties. This variant has been detected in hypertrophic cardiomyopathy and sudden death cohorts; however, details were limited (Marsiglia JD et al. Am Heart J, 2013 Oct;166:775-82; Homburger JR et al. Proc Natl Acad Sci U S A, 2016 06;113:6701-6; Campuzano O et al. Sports Med, 2017 Oct;47:2101-2115). This variant has also been detected in a exome cohort not selected for the presence of cardiovascular disease (Thauvin-Robinet C et al. Eur J Hum Genet, 2019 08;27:1197-1214). This amino acid position is highly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Fulgent Genetics, Fulgent Genetics RCV002485326 SCV002788990 uncertain significance Hypertrophic cardiomyopathy 1; Myopathy, myosin storage, autosomal recessive; Myosin storage myopathy; Congenital myopathy with fiber type disproportion; Dilated cardiomyopathy 1S; MYH7-related skeletal myopathy 2022-04-07 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV003323452 SCV004030128 likely pathogenic Primary familial hypertrophic cardiomyopathy 2023-07-14 criteria provided, single submitter clinical testing Variant summary: MYH7 c.5422G>A (p.Gly1808Ser) results in a non-conservative amino acid change located in the Myosin tail domain (IPR002928) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 3.6e-05 in 251466 control chromosomes. However, the possibility of sub-clinical and/or overt disease in this cohort cannot be entirely excluded, therefore these occurrences do not allow for reliable conclusions regarding variant significance. c.5422G>A has been reported in the literature in cohorts of individuals affected with Hypertrophic Cardiomyopathy or Sudden Cardiac Death (example, Marsiglia_2013, Homburger_2016, Ho_2018, Campuzano_2017, Thauvin-Robert_2019, Park_2021). 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: 28255936, 30297972, 27247418, 24093860, 34542152, 31019283). Seven submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. Multiple submitters reported the variant with conflicting assessments citing overlapping evidence utilized in the context of this evaluation (VUS, n=5; LP, n=2). Based on the evidence outlined above, the variant was classified as likely pathogenic.

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