Submissions for variant NM_000257.4(MYH7):c.4807G>A (p.Ala1603Thr)

gnomAD frequency: 0.00001  dbSNP: rs730880809

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000158670	SCV000208605	uncertain significance	not provided	2022-06-01	criteria provided, single submitter	clinical testing	Reported in association with HCM, including one pediatric patient (Millat et al., 2010; Newman et al., 2018; Ware et al., 2021); 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: 20624503, 29362845, 20800588, 33906374, Shahbazi2020[CaseReport])
Ambry Genetics	RCV000620277	SCV000735988	uncertain significance	Cardiovascular phenotype	2017-08-24	criteria provided, single submitter	clinical testing	The p.A1603T variant (also known as c.4807G>A), located in coding exon 32 of the MYH7 gene, results from a G to A substitution at nucleotide position 4807. The alanine at codon 1603 is replaced by threonine, an amino acid with similar properties. This alteration was reported in a cohort of individuals with hypertrophic cardiomyopathy; however, limited clinical information was provided (Millat G et al. Clin. Chim. Acta, 2010 Dec;411:1983-91). This amino acid position is 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.
Color Diagnostics, LLC DBA Color Health	RCV001183734	SCV001349546	uncertain significance	Cardiomyopathy	2020-03-05	criteria provided, single submitter	clinical testing	This missense variant replaces alanine with threonine at codon 1603 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). Splice site prediction tools suggest that this variant may not impact RNA splicing. To our knowledge, functional studies have not been reported for this variant. This variant has been reported in an individual affected with hypertrophic cardiomyopathy (PMID: 20800588). This variant has been identified in 2/251490 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.
Invitae	RCV001850221	SCV002223822	uncertain significance	Hypertrophic cardiomyopathy	2023-08-02	criteria provided, single submitter	clinical testing	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. This variant disrupts the p.Ala1603 amino acid residue in MYH7. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 24664454, 25214167, 27387980; Invitae). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. ClinVar contains an entry for this variant (Variation ID: 181266). This missense change has been observed in individual(s) with hypertrophic cardiomyopathy (PMID: 20800588, 33906374). This variant is present in population databases (rs730880809, gnomAD 0.007%). This sequence change replaces alanine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 1603 of the MYH7 protein (p.Ala1603Thr).
Fulgent Genetics, Fulgent Genetics	RCV002484978	SCV002797681	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	2021-08-23	criteria provided, single submitter	clinical testing
Revvity Omics, Revvity	RCV000158670	SCV004236716	uncertain significance	not provided	2023-03-21	criteria provided, single submitter	clinical testing