Submissions for variant NM_000257.4(MYH7):c.1681G>A (p.Ala561Thr)

gnomAD frequency: 0.00001  dbSNP: rs730880878

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000158812	SCV000208747	uncertain significance	not provided	2023-05-09	criteria provided, single submitter	clinical testing	In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 25163546, 34426522, 26582918, 34542152, 33996946, 29300372, 27532257, 18258667)
Ambry Genetics	RCV000244373	SCV000320200	uncertain significance	Cardiovascular phenotype	2018-01-10	criteria provided, single submitter	clinical testing	The p.A561T variant (also known as c.1681G>A), located in coding exon 14 of the MYH7 gene, results from a G to A substitution at nucleotide position 1681. The alanine at codon 561 is replaced by threonine, an amino acid with similar properties. This variant was reported in one individual with hypertrophic cardiomyopathy; however, clinical details were limited (Waldmuller et al. Clin Chem. 2008 Apr;54(4):682-7). This amino acid position is poorly 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 variant remains unclear.
Invitae	RCV001064082	SCV001228958	uncertain significance	Hypertrophic cardiomyopathy	2023-10-09	criteria provided, single submitter	clinical testing	This sequence change replaces alanine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 561 of the MYH7 protein (p.Ala561Thr). This variant is present in population databases (rs730880878, gnomAD 0.01%). This missense change has been observed in individual(s) with hypertrophic cardiomyopathy and/or dilated cardiomyopathy (PMID: 18258667, 33996946, 34542152). ClinVar contains an entry for this variant (Variation ID: 181352). 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 not expected to disrupt 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.
Color Diagnostics, LLC DBA Color Health	RCV001190250	SCV001357700	uncertain significance	Cardiomyopathy	2023-03-16	criteria provided, single submitter	clinical testing	This missense variant replaces alanine with threonine at codon 561 of the MYH7 protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). 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: 18258667). It has also been reported in an individual affected with dilated cardiomyopathy who was also a carrier for a pathogenic variant in the TTN gene that could explain the observed phenotype (PMID: 33552729). This variant has been identified in 7/251484 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.