Submissions for variant NM_000257.4(MYH7):c.3589G>A (p.Ala1197Thr)

gnomAD frequency: 0.00001  dbSNP: rs1487430775

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV001216074	SCV001387848	uncertain significance	Hypertrophic cardiomyopathy	2024-02-18	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 1197 of the MYH7 protein (p.Ala1197Thr). This variant is present in population databases (no rsID available, gnomAD 0.0009%). 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: 945432). 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	RCV002491667	SCV002782877	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	2021-10-21	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV003532897	SCV004356842	uncertain significance	Cardiomyopathy	2023-10-05	criteria provided, single submitter	clinical testing	This missense variant replaces alanine with threonine at codon 1197 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 been identified in 1/244122 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.
All of Us Research Program, National Institutes of Health	RCV003532897	SCV004841307	uncertain significance	Cardiomyopathy	2023-11-02	criteria provided, single submitter	clinical testing	This missense variant replaces alanine with threonine at codon 1197 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 been identified in 1/244122 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.
Ambry Genetics	RCV004639499	SCV005143067	uncertain significance	Cardiovascular phenotype	2024-03-21	criteria provided, single submitter	clinical testing	The p.A1197T variant (also known as c.3589G>A), located in coding exon 25 of the MYH7 gene, results from a G to A substitution at nucleotide position 3589. The alanine at codon 1197 is replaced by threonine, 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. Based on the available evidence, the clinical significance of this alteration remains unclear.
GeneDx	RCV005051871	SCV005685921	uncertain significance	not provided	2024-07-25	criteria provided, single submitter	clinical testing	In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Has not been previously published as pathogenic or benign to our knowledge; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 34542152)