Submissions for variant NM_000257.4(MYH7):c.3721G>T (p.Ala1241Ser)

dbSNP: rs757538583

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV001247088	SCV001420490	uncertain significance	Hypertrophic cardiomyopathy	2023-04-10	criteria provided, single submitter	clinical testing	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. 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. ClinVar contains an entry for this variant (Variation ID: 971327). This variant has not been reported in the literature in individuals affected with MYH7-related conditions. This variant is present in population databases (rs757538583, gnomAD 0.003%). This sequence change replaces alanine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 1241 of the MYH7 protein (p.Ala1241Ser).
Color Diagnostics, LLC DBA Color Health	RCV001525590	SCV001735754	uncertain significance	Cardiomyopathy	2022-08-04	criteria provided, single submitter	clinical testing	This missense variant replaces alanine with serine at codon 1241 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 not been reported in individuals affected with cardiovascular disorders in the literature. This variant has been identified in 1/251294 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	RCV002348842	SCV002620262	uncertain significance	Cardiovascular phenotype	2018-11-01	criteria provided, single submitter	clinical testing	The p.A1241S variant (also known as c.3721G>T), located in coding exon 25 of the MYH7 gene, results from a G to T substitution at nucleotide position 3721. The alanine at codon 1241 is replaced by serine, an amino acid with similar properties. This amino acid position is not well conserved in available vertebrate species, and serine is the reference amino acid in other 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.
Neuberg Supratech Reference Laboratories Pvt Ltd, Neuberg Centre for Genomic Medicine	RCV003339564	SCV004047155	uncertain significance	Myosin storage myopathy		criteria provided, single submitter	clinical testing	The missense variant p.A1241S in MYH7 (NM_000257.4) has been submitted to ClinVar as a Variant of Uncertain Significance, but no details are available for independent assessment. The p.A1241S variant has a gnomAD frequency of 0.0003979 % and is novel (not in any individuals) in 1000 Genomes. The amino acid Ala at position 1241 is changed to a Ser changing protein sequence and it might alter its composition and physico-chemical properties. The amino acid change p.Ala1241Ser in MYH7 is predicted as conserved by GERP++ and PhyloP across 100 vertebrates. For these reasons, this variant has been classified as Uncertain Significance.