Submissions for variant NM_000257.4(MYH7):c.211G>A (p.Val71Met)

gnomAD frequency: 0.00004  dbSNP: rs730880830

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000168833	SCV000208660	uncertain significance	not provided	2018-04-11	criteria provided, single submitter	clinical testing	p.Val71Met (GTG>ATG): c.211 G>A in exon 4 of the MYH7 gene (NM_000257.2). A variant of unknown significance has been identified in the MYH7 gene. The V71M variant has not been published as a mutation, nor has it been reported as a benign polymorphism to our knowledge. The V71M 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. Missense mutations in nearby residues (V59I, P81S) have been reported in association with HCM and DCM, respectively, supporting the functional significance of this region of the protein. This substitution occurs at a position that is conserved across species. However, the V71M variant is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties. 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 a pathogenic mutation or a rare benign variant. The variant is found in CARDIOMYOPATHY panel(s).
Invitae	RCV000537548	SCV000623659	uncertain significance	Hypertrophic cardiomyopathy	2024-01-02	criteria provided, single submitter	clinical testing	This sequence change replaces valine, which is neutral and non-polar, with methionine, which is neutral and non-polar, at codon 71 of the MYH7 protein (p.Val71Met). This variant is present in population databases (rs730880830, gnomAD 0.01%). This missense change has been observed in individual(s) with clinical features of dilated cardiomyopathy (PMID: 34490048; Invitae). ClinVar contains an entry for this variant (Variation ID: 181297). 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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001174729	SCV001338008	uncertain significance	not specified	2020-01-06	criteria provided, single submitter	clinical testing	Variant summary: MYH7 c.211G>A (p.Val71Met) results in a conservative amino acid change located in the Myosin, N-terminal, SH3-like domain (IPR004009) 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 5.2e-05 in 251330 control chromosomes (gnomAD). This frequency is not significantly higher than expected for a pathogenic variant in MYH7 causing Cardiomyopathy (5.2e-05 vs 0.0013), allowing no conclusion about variant significance. To our knowledge, no occurrence of c.211G>A in individuals affected with Cardiomyopathy and no experimental evidence demonstrating its impact on protein function have been reported. Two ClinVar submitters (evaluation after 2014) cite the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.
Color Diagnostics, LLC DBA Color Health	RCV001180300	SCV001345195	uncertain significance	Cardiomyopathy	2023-01-27	criteria provided, single submitter	clinical testing	This missense variant replaces valine with methionine at codon 71 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 not been reported in individuals affected with MYH7-related disorders in the literature. This variant has been identified in 14/282710 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.
Fulgent Genetics, Fulgent Genetics	RCV002484983	SCV002794459	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	2021-09-08	criteria provided, single submitter	clinical testing
Revvity Omics, Revvity	RCV000168833	SCV003817770	uncertain significance	not provided	2020-09-24	criteria provided, single submitter	clinical testing
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV001180300	SCV003838775	uncertain significance	Cardiomyopathy	2021-09-10	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV003298186	SCV003993400	uncertain significance	Cardiovascular phenotype	2023-04-26	criteria provided, single submitter	clinical testing	The p.V71M variant (also known as c.211G>A), located in coding exon 2 of the MYH7 gene, results from a G to A substitution at nucleotide position 211. The valine at codon 71 is replaced by methionine, an amino acid with highly similar properties. This alteration has been reported in an infant with an enlarged left ventricle and reduced systolic and diastolic function (Ouyang X et al. Front Genet, 2021 Aug;12:725259). 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.