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

gnomAD frequency: 0.00002  dbSNP: rs369940645

Total submissions: 9

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
Labcorp Genetics (formerly Invitae), Labcorp	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.