Submissions for variant NM_000257.4(MYH7):c.4831G>T (p.Ala1611Ser)

gnomAD frequency: 0.00002  dbSNP: rs730880913

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000158868	SCV000208803	uncertain significance	not provided	2024-07-03	criteria provided, single submitter	clinical testing	Has not been previously published as pathogenic or benign in association with a MYH7-related disorder to our knowledge; 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: 34542152)
Color Diagnostics, LLC DBA Color Health	RCV001181614	SCV001346796	uncertain significance	Cardiomyopathy	2023-05-31	criteria provided, single submitter	clinical testing	This missense variant replaces alanine with serine at codon 1611 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 not been reported in individuals affected with MYH7-related disorders in the literature. This variant has not been identified 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	RCV001366342	SCV001562643	uncertain significance	Hypertrophic cardiomyopathy	2023-11-17	criteria provided, single submitter	clinical testing	This sequence change replaces alanine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 1611 of the MYH7 protein (p.Ala1611Ser). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with MYH7-related conditions. ClinVar contains an entry for this variant (Variation ID: 181392). 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.
Fulgent Genetics, Fulgent Genetics	RCV002492629	SCV002787920	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	2021-09-09	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV003362701	SCV004079294	uncertain significance	Cardiovascular phenotype	2023-09-02	criteria provided, single submitter	clinical testing	The p.A1611S variant (also known as c.4831G>T), located in coding exon 32 of the MYH7 gene, results from a G to T substitution at nucleotide position 4831. The alanine at codon 1611 is replaced by serine, an amino acid with similar properties. 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.
All of Us Research Program, National Institutes of Health	RCV001181614	SCV004830852	uncertain significance	Cardiomyopathy	2024-01-11	criteria provided, single submitter	clinical testing	This missense variant replaces alanine with serine at codon 1611 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 not been reported in individuals affected with MYH7-related disorders in the literature. This variant has not been identified 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.