Submissions for variant NM_000257.4(MYH7):c.3492C>A (p.Asn1164Lys)

dbSNP: rs730880777

Total submissions: 3

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000158609	SCV000208544	uncertain significance	not provided	2013-05-08	criteria provided, single submitter	clinical testing	p.Asn1164Lys (AAC>AAA): c.3492 C>A in exon 27 of the MYH7 gene (NM_000257.2). The Asn1164Lys variant in the MYH7 gene has not been reported as a disease-causing mutation or as a benign polymorphism to our knowledge. Asn1164Lys results in a semi-conservative amino acid substitution of a neutral, polar Asparagine with a positively charged Lysine at a position that is conserved across species. In silico analysis predicts Asn1164Lys is probably damaging to the protein structure/function. The Asn1164Lys variant was not observed in approximately 6,000 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. Nevertheless, no mutations in nearby codons have been reported in association with cardiomyopathy. With the clinical and molecular information available at this time, we cannot definitively determine if Asn1164Lys is a disease-causing mutation or a rare benign variant. The variant is found in HCM panel(s).
Invitae	RCV000688586	SCV000816205	uncertain significance	Hypertrophic cardiomyopathy	2023-12-06	criteria provided, single submitter	clinical testing	This sequence change replaces asparagine, which is neutral and polar, with lysine, which is basic and polar, at codon 1164 of the MYH7 protein (p.Asn1164Lys). 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: 181225). 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.
Ambry Genetics	RCV002453546	SCV002612843	uncertain significance	Cardiovascular phenotype	2023-02-21	criteria provided, single submitter	clinical testing	The p.N1164K variant (also known as c.3492C>A), located in coding exon 25 of the MYH7 gene, results from a C to A substitution at nucleotide position 3492. The asparagine at codon 1164 is replaced by lysine, an amino acid with similar properties. This variant has been detected in an individual from a hypertrophic cardiomyopathy cohort (Murphy SL et al. J Cardiovasc Transl Res. 2016 Apr;9(2):153-61). This amino acid position is highly 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.