Submissions for variant NM_002471.4(MYH6):c.7G>A (p.Asp3Asn)

gnomAD frequency: 0.00011  dbSNP: rs371667049

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000618041	SCV000740081	uncertain significance	Cardiovascular phenotype	2023-03-02	criteria provided, single submitter	clinical testing	The p.D3N variant (also known as c.7G>A), located in coding exon 1 of the MYH6 gene, results from a G to A substitution at nucleotide position 7. The aspartic acid at codon 3 is replaced by asparagine, an amino acid with highly similar properties. This alteration has been reported in a pediatric cardiomyopathy cohort (Ware SM et al. Am J Hum Genet, 2022 Feb;109:282-298). 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.
Labcorp Genetics (formerly Invitae), Labcorp	RCV001309340	SCV001498835	uncertain significance	Hypertrophic cardiomyopathy 14	2025-01-15	criteria provided, single submitter	clinical testing	This sequence change replaces aspartic acid, which is acidic and polar, with asparagine, which is neutral and polar, at codon 3 of the MYH6 protein (p.Asp3Asn). This variant is present in population databases (rs371667049, gnomAD 0.02%). This variant has not been reported in the literature in individuals affected with MYH6-related conditions. ClinVar contains an entry for this variant (Variation ID: 520321). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. 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.
GeneDx	RCV001764736	SCV001998819	uncertain significance	not provided	2023-12-01	criteria provided, single submitter	clinical testing	Has not been previously published as pathogenic or benign to our knowledge; In silico analysis supports that this missense variant has a deleterious effect on protein structure/function
Fulgent Genetics, Fulgent Genetics	RCV002491332	SCV002778482	uncertain significance	Hypertrophic cardiomyopathy 1; Dilated cardiomyopathy 1EE; Hypertrophic cardiomyopathy 14; Atrial septal defect 3; Sick sinus syndrome 3, susceptibility to	2021-08-31	criteria provided, single submitter	clinical testing
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV001764736	SCV004565189	uncertain significance	not provided	2023-01-03	criteria provided, single submitter	clinical testing	The MYH6 c.7G>A; p.Asp3Asn variant (rs371667049), to our knowledge, is not reported in the medical literature but is reported in ClinVar (Variation ID: 520321). This variant is found in the general population with an overall allele frequency of 0.0035% (10/282786 alleles) in the Genome Aggregation Database. The aspartate at codon 3 is moderately conserved and computational analyses are uncertain whether this variant is neutral or deleterious (REVEL: 0.438). Due to limited information, the clinical significance of this variant is uncertain at this time.
Genomic Medicine Center of Excellence, King Faisal Specialist Hospital and Research Centre	RCV003989114	SCV004805689	uncertain significance	Atrial septal defect 3	2024-03-29	criteria provided, single submitter	clinical testing