ClinVar Miner

Submissions for variant NM_000257.4(MYH7):c.3830G>A (p.Arg1277Gln)

gnomAD frequency: 0.00001  dbSNP: rs397516195
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Total submissions: 12
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine RCV000788815 SCV000059520 uncertain significance not provided 2019-04-05 criteria provided, single submitter clinical testing The p.Arg1277Gln variant in MYH7 has been identified in 2 individuals with HCM and 1 individual with left ventricular hypertrophy, though one of these individuals also carried an additional likely disease causing variant in another gene (Zou 2013, LMM data). It has also been identified in 2/66738 European chromosomes by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.org; dbSNP rs397516195). Clinvar: VUS (LMM, GeneDx, Invitae). Computational prediction tools and conservation analysis do not provide strong support for or against an impact to the protein. In summary, the clinical significance of the p.Arg1277Gln variant is uncertain.
GeneDx RCV000035869 SCV000490655 uncertain significance not specified 2016-10-14 criteria provided, single submitter clinical testing A variant of uncertain significance has been identified in the MYH7 gene. The R1277Q variant has been reported in two Chinese patients with HCM; however, one patient also harbored a loss of function variant in the MYBPC3 gene (Zou et al., 2013). Additionally, this variant has been classified as a variant of uncertain significance by another clinical laboratory in ClinVar (SCV000059520.4; Landrum et al., 2016). The R1277Q variant 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 R1277Q variant is a semi-conservative amino acid substitution, which may impact secondary protein structure as these residues differ in some properties. However, this substitution occurs at a position where amino acids with similar properties to Arginine are tolerated across species and in silico analysis is inconsistent in its predictions as to whether or not the variant is damaging to the protein structure/function. Therefore, based on the currently available information, it is unclear whether this variant is pathogenic or rare benign.
Labcorp Genetics (formerly Invitae), Labcorp RCV000475071 SCV000546269 uncertain significance Hypertrophic cardiomyopathy 2023-12-17 criteria provided, single submitter clinical testing This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 1277 of the MYH7 protein (p.Arg1277Gln). This variant is present in population databases (rs397516195, gnomAD 0.009%). This missense change has been observed in individual(s) with hypertrophic cardiomyopathy (PMID: 23283745, 27532257). ClinVar contains an entry for this variant (Variation ID: 42976). 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 with a positive predictive value of 95%. 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.
Fulgent Genetics, Fulgent Genetics RCV000765160 SCV000896389 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 2021-07-28 criteria provided, single submitter clinical testing
Blueprint Genetics RCV000788815 SCV000928071 uncertain significance not provided 2018-11-21 criteria provided, single submitter clinical testing
Color Diagnostics, LLC DBA Color Health RCV001189926 SCV001357320 uncertain significance Cardiomyopathy 2023-03-09 criteria provided, single submitter clinical testing This missense variant replaces arginine with glutamine at codon 1277 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 individuals affected with hypertrophic cardiomyopathy (PMID: 23283745, 27532257, 31104103). Some of these individuals also carried pathogenic variants in the MYBPC3 and MYL2 genes that could explain the observed phenotype (PMID: 23283745, 31104103). This variant has also been reported in a family affected with myosin storage myopathy (DOI:10.21203/rs.2.19928/v1). This variant has been identified in 12/251468 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.
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario RCV001189926 SCV002042671 uncertain significance Cardiomyopathy 2020-09-30 criteria provided, single submitter clinical testing
Revvity Omics, Revvity RCV000788815 SCV003815406 uncertain significance not provided 2020-12-29 criteria provided, single submitter clinical testing
Dept of Medical Biology, Uskudar University RCV003318340 SCV004022059 uncertain significance Long QT syndrome 2024-01-08 criteria provided, single submitter research Criteria: PM2, PP2
PreventionGenetics, part of Exact Sciences RCV004528171 SCV004109238 uncertain significance MYH7-related disorder 2023-03-28 criteria provided, single submitter clinical testing The MYH7 c.3830G>A variant is predicted to result in the amino acid substitution p.Arg1277Gln. This variant has been reported in individuals with hypertrophic cardiomyopathy (Zou et al. 2013. PubMed ID: 23283745; Table S1B, Walsh et al. 2016. PubMed ID: 27532257). However, this variant has also reported in control populations (Table S6, Park et al. 2022. PubMed ID: 34542152) and is reported in 0.0087% of alleles in individuals of Latino descent in gnomAD (http://gnomad.broadinstitute.org/variant/14-23888715-C-T). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.
All of Us Research Program, National Institutes of Health RCV001189926 SCV004816630 uncertain significance Cardiomyopathy 2023-12-13 criteria provided, single submitter clinical testing This missense variant replaces arginine with glutamine at codon 1277 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 individuals affected with hypertrophic cardiomyopathy (PMID: 23283745, 27532257, 31104103). Some of these individuals also carried pathogenic variants in the MYBPC3 and MYL2 genes that could explain the observed phenotype (PMID: 23283745, 31104103). This variant has also been reported in a family affected with myosin storage myopathy (DOI:10.21203/rs.2.19928/v1). This variant has been identified in 12/251468 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.
Ambry Genetics RCV004017299 SCV004849157 uncertain significance Cardiovascular phenotype 2019-10-11 criteria provided, single submitter clinical testing The c.3830G>A (p.R1277Q) alteration is located in exon 28 (coding exon 26) of the MYH7 gene. This alteration results from a G to A substitution at nucleotide position 3830, causing the arginine (R) at amino acid position 1277 to be replaced by a glutamine (Q). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear.

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