Submissions for variant NM_000257.4(MYH7):c.2974C>A (p.Leu992Met)

gnomAD frequency: 0.00001  dbSNP: rs149840927

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000158581	SCV000208516	uncertain significance	not provided	2023-05-04	criteria provided, single submitter	clinical testing	Identified in patients with cardiomyopathy in published literature (Coppini et al., 2014; Homburger et al., 2016); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 25524337, 27247418, 23403236)
Color Diagnostics, LLC DBA Color Health	RCV001187171	SCV001353886	uncertain significance	Cardiomyopathy	2019-06-01	criteria provided, single submitter	clinical testing	This missense variant replaces leucine with methionine at codon 992 of the MYH7 protein. Computational prediction tools and conservation analyses suggest that this variant may have deleterious impact on the protein function. Computational splicing tools suggest that this variant may not impact RNA splicing. To our knowledge, functional assays have not been performed for this variant. This variant has been reported in an individual affected with hypertrophic cardiomyopathy (PMID: 25524337). This variant has also been identified in 2/251490 chromosomes in the general population by the Genome Aggregation Database (gnomAD). 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.
Invitae	RCV001306134	SCV001495493	uncertain significance	Hypertrophic cardiomyopathy	2022-05-04	criteria provided, single submitter	clinical testing	Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). This sequence change replaces leucine, which is neutral and non-polar, with methionine, which is neutral and non-polar, at codon 992 of the MYH7 protein (p.Leu992Met). This variant is present in population databases (rs149840927, gnomAD 0.0009%). This missense change has been observed in individual(s) with hypertrophic cardiomyopathy (PMID: 25524337, 27247418). ClinVar contains an entry for this variant (Variation ID: 181208). 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.
Ambry Genetics	RCV003298182	SCV003993399	uncertain significance	Cardiovascular phenotype	2023-04-21	criteria provided, single submitter	clinical testing	The p.L992M variant (also known as c.2974C>A), located in coding exon 22 of the MYH7 gene, results from a C to A substitution at nucleotide position 2974. The leucine at codon 992 is replaced by methionine, an amino acid with highly similar properties. This variant has been detected in cohorts with hypertrophic cardiomyopathy (Homburger JR et al. Proc Natl Acad Sci U S A, 2016 Jun;113:6701-6; Coppini R et al. J Am Coll Cardiol, 2014 Dec;64:2589-2600). 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.
CeGaT Center for Human Genetics Tuebingen	RCV000158581	SCV004702936	uncertain significance	not provided	2024-02-01	criteria provided, single submitter	clinical testing	MYH7: PM2, PP3, PS4:Supporting