Submissions for variant NM_000257.4(MYH7):c.3035C>A (p.Ala1012Asp)

gnomAD frequency: 0.00002  dbSNP: rs779973529

Total submissions: 11

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Illumina Laboratory Services, Illumina	RCV003320163	SCV000386083	uncertain significance	Myosin storage myopathy	2018-01-12	criteria provided, single submitter	clinical testing	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease.
Illumina Laboratory Services, Illumina	RCV000379421	SCV000386084	likely benign	MYH7-related skeletal myopathy	2018-01-12	criteria provided, single submitter	clinical testing	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease.
Illumina Laboratory Services, Illumina	RCV000320862	SCV000386086	uncertain significance	Dilated Cardiomyopathy, Dominant	2016-06-14	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV000378340	SCV000386087	uncertain significance	Hypertrophic cardiomyopathy 1	2018-01-12	criteria provided, single submitter	clinical testing	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease.
Illumina Laboratory Services, Illumina	RCV000290926	SCV000386088	uncertain significance	Left ventricular noncompaction cardiomyopathy	2016-06-14	criteria provided, single submitter	clinical testing
GeneDx	RCV000489125	SCV000577229	uncertain significance	not provided	2022-12-07	criteria provided, single submitter	clinical testing	Identified in an individual with dilated cardiomyopathy and reported as a variant of uncertain clinical significance (Ramchand et al., 2020); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 31931689, 34008892)
Color Diagnostics, LLC DBA Color Health	RCV000777729	SCV000913680	uncertain significance	Cardiomyopathy	2023-06-09	criteria provided, single submitter	clinical testing	This missense variant replaces alanine with aspartic acid at codon 1012 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 been reported in one individual affected with dilated cardiomyopathy (PMID: 31931689). It has also been reported in one individual affected with cardiomyopathy, nephrotic syndrome, focal segmental glomerulosclerosis, and beta-thalassemia (PMID: 34008892). This variant has been identified in 6/251492 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.
Invitae	RCV001364427	SCV001560576	uncertain significance	Hypertrophic cardiomyopathy	2023-10-28	criteria provided, single submitter	clinical testing	This sequence change replaces alanine, which is neutral and non-polar, with aspartic acid, which is acidic and polar, at codon 1012 of the MYH7 protein (p.Ala1012Asp). This variant is present in population databases (rs779973529, gnomAD 0.004%). This missense change has been observed in individual(s) with dilated cardiomyopathy (PMID: 31931689). ClinVar contains an entry for this variant (Variation ID: 312903). 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.
Laboratory of Medical Genetics, National & Kapodistrian University of Athens	RCV001729526	SCV001976904	uncertain significance	Dilated cardiomyopathy 1S	2021-10-06	criteria provided, single submitter	clinical testing	PM2, PP2, PP3
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV000777729	SCV002042661	uncertain significance	Cardiomyopathy	2020-11-19	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV002436162	SCV002753456	uncertain significance	Cardiovascular phenotype	2021-07-19	criteria provided, single submitter	clinical testing	The p.A1012D variant (also known as c.3035C>A), located in coding exon 22 of the MYH7 gene, results from a C to A substitution at nucleotide position 3035. The alanine at codon 1012 is replaced by aspartic acid, an amino acid with dissimilar properties. This variant was detected in a dilated cardiomyopathy cohort; however, clinical details were limited (Ramchand J et al. J Am Heart Assoc, 2020 01;9:e013346). This amino acid position is well 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.