Submissions for variant NM_000257.4(MYH7):c.4010G>A (p.Arg1337Gln)

gnomAD frequency: 0.00005  dbSNP: rs368575559

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000158627	SCV000208562	uncertain significance	not provided	2021-11-09	criteria provided, single submitter	clinical testing	Reported in one patient with HCM and one patient with left ventricular hypertrabeculation (Berge et al., 2014; Miszalski-Jamka et al., 2017); In silico analysis supports that this missense variant does not alter protein structure/function; Reported in ClinVar as a variant of uncertain significance (ClinVar Variant ID#181238; Landrum et al., 2016); This variant is associated with the following publications: (PMID: 24111713, 25649125, 22958901, 28798025, 26582918)
Ambry Genetics	RCV000619617	SCV000740099	likely benign	Cardiovascular phenotype	2022-10-12	criteria provided, single submitter	clinical testing	This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.
Color Diagnostics, LLC DBA Color Health	RCV000778008	SCV000914117	uncertain significance	Cardiomyopathy	2023-04-28	criteria provided, single submitter	clinical testing	This missense variant replaces arginine with glutamine at codon 1337 of the MYH7 protein. Computational prediction suggests that this variant may have a deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). To our knowledge, functional studies have not been performed for this variant. This variant has been reported in an individual affected with hypertrophic cardiomyopathy (PMID: 24111713) and in an individual affected with left ventricular hypertrabeculation (PMID: 28798025). This variant has been identified in 34/281574 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The elevated variant allele frequency in the general population indicates that this variant may not be disease-causing. However, additional studies are necessary to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.
Labcorp Genetics (formerly Invitae), Labcorp	RCV001225105	SCV001397341	uncertain significance	Hypertrophic cardiomyopathy	2023-12-31	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 1337 of the MYH7 protein (p.Arg1337Gln). This variant is present in population databases (rs368575559, gnomAD 0.06%). This missense change has been observed in individual(s) with left ventricular noncompaction or hypertrophic cardiomyopathy (PMID: 24111713, 28798025). ClinVar contains an entry for this variant (Variation ID: 181238). 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) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on MYH7 protein function. 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	RCV002492624	SCV002791520	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	2021-12-01	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV000158627	SCV003917316	uncertain significance	not provided	2023-02-01	criteria provided, single submitter	clinical testing	MYH7: PP2, PP3
All of Us Research Program, National Institutes of Health	RCV000778008	SCV004814387	uncertain significance	Cardiomyopathy	2024-02-05	criteria provided, single submitter	clinical testing	This missense variant replaces arginine with glutamine at codon 1337 of the MYH7 protein. Computational prediction suggests that this variant may have a deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). To our knowledge, functional studies have not been performed for this variant. This variant has been reported in an individual affected with hypertrophic cardiomyopathy (PMID: 24111713) and in an individual affected with left ventricular hypertrabeculation (PMID: 28798025). This variant has been identified in 34/281574 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The elevated variant allele frequency in the general population indicates that this variant may not be disease-causing. However, additional studies are necessary to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.
Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	RCV000158627	SCV001798041	uncertain significance	not provided		no assertion criteria provided	clinical testing
Clinical Genetics, Academic Medical Center	RCV000158627	SCV001923752	uncertain significance	not provided		no assertion criteria provided	clinical testing