Submissions for variant NM_000256.3(MYBPC3):c.845G>A (p.Arg282Gln)

gnomAD frequency: 0.00001  dbSNP: rs761520688

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000628950	SCV000749858	uncertain significance	Hypertrophic cardiomyopathy	2023-08-28	criteria provided, single submitter	clinical testing	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 tolerated. 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. ClinVar contains an entry for this variant (Variation ID: 524999). This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 282 of the MYBPC3 protein (p.Arg282Gln). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This variant has not been reported in the literature in individuals affected with MYBPC3-related conditions.
Color Diagnostics, LLC DBA Color Health	RCV001182263	SCV001347655	uncertain significance	Cardiomyopathy	2023-08-28	criteria provided, single submitter	clinical testing	This missense variant replaces arginine with glutamine at codon 282 of the MYBPC3 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 MYBPC3-related disorders in the literature. This variant has been identified in 2/186332 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.
GeneDx	RCV000786364	SCV001778238	uncertain significance	not provided	2023-03-27	criteria provided, single submitter	clinical testing	Has not been previously published as pathogenic or benign to our knowledge; Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant does not alter protein structure/function
All of Us Research Program, National Institutes of Health	RCV000628950	SCV004834708	uncertain significance	Hypertrophic cardiomyopathy	2024-05-14	criteria provided, single submitter	clinical testing	This missense variant replaces arginine with glutamine at codon 282 of the MYBPC3 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 MYBPC3-related disorders in the literature. This variant has been identified in 2/186332 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	RCV004025341	SCV005033881	uncertain significance	Cardiovascular phenotype	2024-01-08	criteria provided, single submitter	clinical testing	The p.R282Q variant (also known as c.845G>A), located in coding exon 8 of the MYBPC3 gene, results from a G to A substitution at nucleotide position 845. The arginine at codon 282 is replaced by glutamine, an amino acid with highly similar properties. 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.
Stanford Center for Inherited Cardiovascular Disease, Stanford University	RCV000786364	SCV000925162	uncertain significance	not provided	2018-02-06	no assertion criteria provided	provider interpretation	Found in a 23-year-old female with unexplained postpartum sudden cardiac arrest, along with 5 other VUSs. p.Arg282Gln (c.845G>A) in exon 8 of the MYBPC3 gene (NM_000256.3; ENST00000545968.5) Chromosome location 11:47369208 C / T Based on the information reviewed below, we classify this as a Variant of Uncertain Significance (VUS). This variant has not been reported in the literature in association with disease, according to the Invitae report. This is a nonconservative amino acid change, resulting in the replacement of a positively-charged Arginine with a polar, uncharged Glutamine. Arginine at this location is highly conserved across the vertebrate species for which we have data. There are no Likely Pathogenic or Pathogenic missense variants listed in ClinVar within 10 amino acids to either side, indicating that this region of the protein might be tolerant of missense change. According to the Invitae report, a computational algorithm designed to assess the pathogenicity of variants in MYBPC3 with regard to hypertrophic cardiomyopathy predicted this sequence change to be tolerated. The algorithm has a sensitivity of 94% and a specificity of 89% (PMID: 21310275). This variant was reported in 2 out of the 90,673 individuals in the gnomAD database for which there are variant calls (1 Latino and 1 South Asian). This may indicate a low-quality sequencing site since there are ~140,000 individuals of European, African, Latino, South Asian, Ashkenazi, and East Asian descent in the database. Overall MAF: 0.001%. Another variant at this site, p.Arg282Trp, is present in 2 individuals out of only 15,415 for which there are calls. The phenotype of those individuals is not publicly available. The dataset is comprised of multiple cohorts, some of which were recruited from the general population, others were enriched for common cardiovascular disease. The curators made an effort to exclude individuals with severe pediatric diseases.