Submissions for variant NM_000257.4(MYH7):c.1630A>G (p.Thr544Ala)

gnomAD frequency: 0.00001  dbSNP: rs397516119

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000035739	SCV000059390	uncertain significance	not specified	2014-01-19	criteria provided, single submitter	clinical testing	proposed classification - variant undergoing re-assessment, contact laboratory
Fulgent Genetics, Fulgent Genetics	RCV000763913	SCV000894854	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	2021-10-02	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV001524577	SCV001734473	uncertain significance	Cardiomyopathy	2023-08-02	criteria provided, single submitter	clinical testing	This missense variant replaces threonine with alanine at codon 544 of the MYH7 protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in an individual affected with dilated cardiomyopathy (PMID: 24503780). This variant has been identified in 3/251454 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.
Labcorp Genetics (formerly Invitae), Labcorp	RCV003114212	SCV003785854	uncertain significance	Hypertrophic cardiomyopathy	2023-12-19	criteria provided, single submitter	clinical testing	This sequence change replaces threonine, which is neutral and polar, with alanine, which is neutral and non-polar, at codon 544 of the MYH7 protein (p.Thr544Ala). This variant is present in population databases (rs397516119, gnomAD 0.003%). This missense change has been observed in individual(s) with dilated cardiomyopathy (PMID: 27532257). ClinVar contains an entry for this variant (Variation ID: 42858). 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.
Ambry Genetics	RCV003298053	SCV003993378	uncertain significance	Cardiovascular phenotype	2023-03-29	criteria provided, single submitter	clinical testing	The p.T544A variant (also known as c.1630A>G), located in coding exon 14 of the MYH7 gene, results from an A to G substitution at nucleotide position 1630. The threonine at codon 544 is replaced by alanine, an amino acid with similar properties. This alteration has been reported in a dilated cardiomyopathy (DCM) cohort; however, clinical details were limited (Pugh TJ et al. Genet Med, 2014 Aug;16:601-8; Walsh R et al. Genet Med, 2017 Feb;19:192-203). This amino acid position is not well conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV001524577	SCV004239441	uncertain significance	Cardiomyopathy	2023-05-16	criteria provided, single submitter	clinical testing
All of Us Research Program, National Institutes of Health	RCV001524577	SCV004826600	uncertain significance	Cardiomyopathy	2023-08-15	criteria provided, single submitter	clinical testing	This missense variant replaces threonine with alanine at codon 544 of the MYH7 protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in an individual affected with dilated cardiomyopathy (PMID: 24503780). This variant has been identified in 3/251454 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.
GeneDx	RCV003322748	SCV004028138	likely pathogenic	not provided	2023-08-16	flagged submission	clinical testing	Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 27532257, 29300372, 24503780)