ClinVar Miner

Submissions for variant NM_000257.4(MYH7):c.5326A>G (p.Ser1776Gly) (rs369437262)

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Total submissions: 11
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
ClinGen Inherited Cardiomyopathy Variant Curation Expert Panel, RCV000462813 SCV000564457 uncertain significance Hypertrophic cardiomyopathy 2016-12-15 reviewed by expert panel curation The c.5326A>G (p.Ser1776Gly) variant in MYH7 has been reported in 12 individuals with hypertrophic cardiomyopathy (PMID:27532257; PMID:11861413; PMID:21239446; Partners LMM ClinVar SCV000203861.4; SHaRe consortium, PMID: 30297972) but has also been identified in 0.02% (2/8654) of East Asian chromosomes by ExAC ( Since the MYH7 specifications state that PS4 is only applicable if the variant is absent or rare in large population studies, PS4 criterion was not applied (PMID:29300372). 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 uncertain significance for hypertrophic cardiomyopathy in an autosomal dominant manner. MYH7-specific ACMG/AMP criteria applied (PMID:29300372): PP3
Laboratory for Molecular Medicine, Partners HealthCare Personalized Medicine RCV000154209 SCV000203861 uncertain significance not specified 2018-11-29 criteria provided, single submitter clinical testing The p.Ser1776Gly variant in MYH7 has been identified in at least 12 individuals with HCM (Blair 2002, Fokstuen 2010, Homburger 2016, Walsh 2017, Kelly 2018, Ho 2018, LMM data) and segregated with disease in 1 affected family member (Blair 2 002). It has also been identified in 0.03% (6/19954) of East Asian and 0.02% (5/ 24968) of African chromosomes by gnomAD ( Comp utational prediction tools and conservation analysis suggest that this variant m ay impact the protein, though this information is not predictive enough to deter mine pathogenicity. Moreover, this variant was classified as a variant of uncert ain significance on December 15, 2016 by the ClinGen-approved Inherited Cardiomy opathy expert panel (SCV000564457.2). In summary, the clinical significance of t he p.Ser1776Gly variant is uncertain due to conflicting evidence. ACMG/AMP Crite ria applied: PP3.
GeneDx RCV000154209 SCV000208629 uncertain significance not specified 2017-05-09 criteria provided, single submitter clinical testing The S1776G variant was identified in two siblings with HCM but failed to segregate in a third sibling, and was absent from 400 population-matched control chromosomes (Blair et al., 2002). Additionally, S1776G was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. The S1776G variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. This substitution occurs at a position that is conserved across species. However, in silico analysis is inconsistent in its predictions as to whether or not the variant is damaging to the protein structure/function. Furthermore, the S1776G variant has been observed in multiple other presumably unrelated individuals tested for cardiomyopathy at GeneDx, several of whom are noted to be of Asian ancestry, indicating S1776G might be a rare variant in this population. Two of these individuals also harbored a known pathogenic variant associated with cardiomyopathy. Therefore, based on the currently available information, it is unclear whether this variant is pathogenic or rare benign.
Invitae RCV000462813 SCV000546233 uncertain significance Hypertrophic cardiomyopathy 2019-12-20 criteria provided, single submitter clinical testing This sequence change replaces serine with glycine at codon 1776 of the MYH7 protein (p.Ser1776Gly). The serine residue is highly conserved and there is a small physicochemical difference between serine and glycine. This variant is present in population databases (rs369437262, ExAC 0.02%). This variant has been reported in two individuals of a single family affected with hypertrophic cardiomyopathy, as well as several unrelated individuals with hypertrophic cardiomyopathy (PMID: 11861413, 27247418, 27532257, 29121657). However, the majority of individuals reported with this variant are of Pacific Islander/Asian ancestry for which there is insufficient population data to determine the frequency of this variant in the general population (PMID: 28518168) and one individual carried an additional variant in MYBPC3 (PMID: 29121657). ClinVar contains an entry for this variant (Variation ID: 177629). Experimental studies have shown that this missense change does not affect binding of myosin-binding protein-C (PMID: 16918501). However the clinical significance of this result is unknown. 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.
Center for Pediatric Genomic Medicine,Children's Mercy Hospital and Clinics RCV000514376 SCV000609658 uncertain significance not provided 2017-04-19 criteria provided, single submitter clinical testing
Ambry Genetics RCV000620185 SCV000736987 uncertain significance Cardiovascular phenotype 2018-05-31 criteria provided, single submitter clinical testing Insufficient evidence
Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease,Montreal Heart Institute RCV000168915 SCV000740371 uncertain significance Primary familial hypertrophic cardiomyopathy 2016-05-18 criteria provided, single submitter clinical testing
Fulgent Genetics,Fulgent Genetics RCV000765157 SCV000896386 uncertain significance Familial hypertrophic cardiomyopathy 1; Myopathy, myosin storage, autosomal recessive; Myosin storage myopathy; Congenital myopathy with fiber type disproportion; Dilated cardiomyopathy 1S; Myopathy, distal, 1; MYH7-related late-onset scapuloperoneal muscular dystrophy 2018-10-31 criteria provided, single submitter clinical testing
CHEO Genetics Diagnostic Laboratory,Children's Hospital of Eastern Ontario RCV001170485 SCV001333066 uncertain significance Cardiomyopathy 2018-07-23 criteria provided, single submitter clinical testing
Color RCV001170485 SCV001359756 uncertain significance Cardiomyopathy 2019-12-01 criteria provided, single submitter clinical testing
Stanford Center for Inherited Cardiovascular Disease, Stanford University RCV000154209 SCV000280364 uncertain significance not specified 2015-01-06 no assertion criteria provided clinical testing Note this variant was found in clinical genetic testing performed by one or more labs who may also submit to ClinVar. Thus any internal case data may overlap with the internal case data of other labs. The interpretation reviewed below is that of the Stanford Center for Inherited Cardiovascular Disease. p.Ser1776Gly (AGC>GGC): c.5326 A>G in exon 37 of the MYH7 gene (NM_000257.2) We first reviewed this variant in 2011. We re-reviewed them October 15th, 2014 and then again February 20th, 2015. Given the high frequency of Filipino cases and lack of ancestry matched controls we consider this a variant of uncertain significance. The variant has been seen in two published cases of HCM and at least 15 unpublished cases (not including the patient). Ancestry is only available for 11 cases (including this patient); 5 are Asian, 6 are Filipino of those are Asian, as is this patient. At least 4 of 16 total cases (including ours) have another sarcomere variant. This variant has been reported previously in two unrelated cases of HCM (Blair et al 2002, Fokstuen et al 2010). In the family reported by Blair et al (2002) the variant was present in two affected siblings and absent in an unaffected sibling (ancestry not reported). The proband underwent analysis of MYH7, MYBPC3, TNNT2, ACTC2, MYL2 and had no variants in those genes. Cases were recruited in the UK and South Africa.Fokstuen et al (2010) observed the variant in 1 of 122 unrelated HCM patients recruited in Switzerland. They did not provide segregation data. Subjects underwent sequencing of MYH7, MYBPC3, TNNT2, TPM1, TNNI3, MYL3, MYL2, CSRP3, PLN, ACTC1, TNNC1, PRKAG2, however the authors do not report if any cases had multiple variants. We have seen the variant in one other patient with HCM in our center who is Fillipino. This is a semi conservative amino acid change with a polar Serine replaced with a nonpolar Glycine at codon 1776 of MYH7 gene. The Serine at position 1776 is conserved across mammals and myosin isoforms. Given that this amino acid change is located in a core position of the myosin rod, where a Glycine is expected to be energetically unfavorable, Blair et al (2002) hypothesized that this variant would disrupt the normal coiled-coil structure of myosin. However, this variant did not interfere with binding to myosin binding protein C (Flasshman et al 2007). Variants in nearby codons have been reported in association with cardiomyopathy: p.Glu1768Lys (van Driest et al 2003), p.Thr1775Ile (Bos et al 2014), p.Ala1777Thr (Richard et al 2003, Bos et al 2014), p.His1778Tyr (Alfares et al 2015), . The variant was reported online in 4 of 60705 individuals in the Exome Aggregation Consortium dataset (, which currently includes variant calls on ~64,000 individuals of European, African, Latino and Asian descent (as of February 23rd, 2015). Specifically, the variant was observed in 2 of 4327 East Asians and 2 of 5203 Africans, . The phenotype of those individuals is not publicly available. The dataset is comprised of multiple cohorts, some of which were recruited from the general population, others were enriched for common cardiovascular disease. Note that other variants with strong evidence for pathogenicity have been seen at similar frequencies in datasets like this so this does not necessarily rule out pathogenicity (Pan et al 2012). Blair et al (2002) report they did not observe the variant in 200 presumably healthy control individuals. Fokstuen et al (2010) did not analyze teh variant in controls.

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