Submissions for variant NM_000257.4(MYH7):c.3883G>A (p.Glu1295Lys)

gnomAD frequency: 0.00001  dbSNP: rs730880785

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen Cardiomyopathy Variant Curation Expert Panel	RCV001797640	SCV002041484	uncertain significance	Cardiomyopathy	2021-11-19	reviewed by expert panel	curation	The NM_000257.4(MYH7):c.3883G>A (p.Glu1295Lys) variant has been identified in 1 individual with LVNC, in 1 individual with congestive heart failure and 1 individual with sudden cardiac arrest (GeneDx pers. comm., Invitae pers. comm.); however, due to the nature of the associated phenotypes, this data is insufficient to apply the PS4 criterion. This variant was identified in 0.002% (FAF 95% CI; 3/34592) of Latino/Admixed American chromosomes by gnomAD v2.1.1 (PM2; https://gnomad.broadinstitute.org). Computational prediction tools and conservation analysis suggest that this variant may impact the protein (PP3). In summary, due to insufficient evidence, this variant is classified as uncertain significance for cardiomyopathy in an autosomal dominant manner. MYH7-specific ACMG/AMP criteria applied (Kelly 2018 PMID:29300372): PM2, PP3.
GeneDx	RCV000158623	SCV000208558	likely pathogenic	not provided	2014-07-29	criteria provided, single submitter	clinical testing	p.Glu1295Lys (GAG>AAG): c.3883 G>A in exon 29 of the MYH7 gene (NM_000257.2). A E1295K variant that is likely pathogenic was identified in the MYH7 gene. The E1295K variant has not been published as a mutation, nor has it been reported as a benign polymorphism to our knowledge. The E1295K 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 E1295K 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. In silico analysis predicts this variant is probably damaging to the protein structure/function. This substitution occurs at a position that is class conserved across species. Additionally, missense mutations in nearby residues (E1286K, L1297V) have been reported in association with cardiomyopathy, supporting the functional importance of this region of the protein. Therefore, this variant is a strong candidate for a pathogenic mutation, however the possibility that it is a benign variant cannot be excluded. The variant is found in DCM-CRDM panel(s).
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000780520	SCV000917847	uncertain significance	not specified	2018-10-24	criteria provided, single submitter	clinical testing	Variant summary: MYH7 c.3883G>A (p.Glu1295Lys) results in a conservative amino acid change located in the Myosin tail 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 1.2e-05 in 246272 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. To our knowledge, no occurrence of c.3883G>A in individuals affected with Cardiomyopathy and no experimental evidence demonstrating its impact on protein function have been reported. Although nearby missense changes, p.L1297Q, p.L1297V, p.Q1300L, have been reported in affected individuals suggesting that this region could be important for protein function. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014. Based on the evidence outlined above, the variant was classified as uncertain significance.
Labcorp Genetics (formerly Invitae), Labcorp	RCV001233105	SCV001405686	uncertain significance	Hypertrophic cardiomyopathy	2023-07-08	criteria provided, single submitter	clinical testing	This variant is present in population databases (rs730880785, gnomAD 0.009%). 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. 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: 181236). This variant has not been reported in the literature in individuals affected with MYH7-related conditions. This sequence change replaces glutamic acid, which is acidic and polar, with lysine, which is basic and polar, at codon 1295 of the MYH7 protein (p.Glu1295Lys).
Fulgent Genetics, Fulgent Genetics	RCV002484975	SCV002777907	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	2022-04-03	criteria provided, single submitter	clinical testing
All of Us Research Program, National Institutes of Health	RCV001797640	SCV004831285	uncertain significance	Cardiomyopathy	2023-12-13	criteria provided, single submitter	clinical testing	This missense variant replaces glutamic acid with lysine at codon 1295 of the MYH7 protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 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 3/251486 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.