ClinVar Miner

Submissions for variant NM_000256.3(MYBPC3):c.1786G>A (p.Gly596Arg) (rs199728019)

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Total submissions: 11
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Laboratory for Molecular Medicine, Partners HealthCare Personalized Medicine RCV000035433 SCV000059081 uncertain significance not specified 2018-04-10 criteria provided, single submitter clinical testing proposed classification - variant undergoing re-assessment, contact laboratory
GeneDx RCV000656917 SCV000208048 uncertain significance not provided 2018-05-16 criteria provided, single submitter clinical testing The G596R variant of uncertain significance in the MYBPC3 gene has previously been reported in several unrelated individuals with HCM and one adult individual with unexplained sudden death (Chung et al., 2007; Gruner et al., 2011; Alfares et al., 2015; Lopes et al., 2015; Sanchez et al., 2017); however, detailed clinical information was often not provided. Chung et al. (2007) reported siblings with HCM who also harbored a variant in the MYH7 gene; family segregation studies were uninformative and several individuals with normal echocardiograms harbored one or both of the variants. The G596R variant has also been identified in multiple unrelated probands referred for cardiomyopathy genetic testing at GeneDx. However, many of these individuals harbored additional disease-related variants, and segregation data are currently limited due to lack of clinical information provided. The G596R variant is observed in 13/8,864 (0.15%) alleles from individuals of Ashkenazi Jewish descent in large population cohorts (Lek et al., 2016), indicating it may be a rare benign variant in this population. Nevertheless, the G596R variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. Moreover, in-silico analyses, including protein predictors and evolutionary conservation, support a deleterious effect. Therefore, based on the currently available information, it is unclear whether this variant is pathogenic or benign.
Invitae RCV001083913 SCV000259413 likely benign Hypertrophic cardiomyopathy 2020-12-01 criteria provided, single submitter clinical testing
Ambry Genetics RCV000250820 SCV000320153 uncertain significance Cardiovascular phenotype 2019-03-12 criteria provided, single submitter clinical testing The p.G596R variant (also known as c.1786G>A), located in coding exon 18 of the MYBPC3 gene, results from a G to A substitution at nucleotide position 1786. The glycine at codon 596 is replaced by arginine, an amino acid with dissimilar properties. This variant has been described in hypertrophic cardiomyopathy (HCM) cohorts; however, clinical details were limited (Gruner et al. Circ Cardiovasc Genet. 2011;4(3):288-95; Lopes et al. Heart. 2015;101(4):294-301). Another study reported this variant in a patient with elderly-onset HCM and severe pulmonary hypertension in addition to a pulmonary arteriovenous malformation (Arad et al. Isr Med Assoc. 2014;16(11):707-13). This amino acid position is highly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Color Health, Inc RCV000777875 SCV000913882 uncertain significance Cardiomyopathy 2020-11-18 criteria provided, single submitter clinical testing This missense variant replaces glycine with arginine at codon 596 of the MYBPC3 protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in several individuals affected with hypertrophic cardiomyopathy (PMID: 21511876, 25351510, 25558701). This variant has also been identified in 21/203560 chromosomes (14/9070 Ashkenazi Jewish chromosomes) in the general population by the Genome Aggregation Database (gnomAD). Although the elevated allele frequency in the general population suggests that this variant may not be disease-causing, additional studies are necessary to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.
Illumina Clinical Services Laboratory,Illumina RCV001108397 SCV001265626 benign Left ventricular noncompaction 10 2019-04-19 criteria provided, single submitter clinical testing This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases was too high to be consistent with this variant causing disease. Therefore, this variant is classified as benign.
Illumina Clinical Services Laboratory,Illumina RCV001108398 SCV001265627 uncertain significance Familial hypertrophic cardiomyopathy 4 2019-04-19 criteria provided, single submitter clinical testing This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.
CHEO Genetics Diagnostic Laboratory,Children's Hospital of Eastern Ontario RCV000777875 SCV001333606 uncertain significance Cardiomyopathy 2018-05-30 criteria provided, single submitter clinical testing
Mayo Clinic Laboratories, Mayo Clinic RCV000656917 SCV001713565 uncertain significance not provided 2020-12-29 criteria provided, single submitter clinical testing
Blueprint Genetics RCV000157307 SCV000207042 likely pathogenic Primary familial hypertrophic cardiomyopathy 2014-10-31 no assertion criteria provided clinical testing
Stanford Center for Inherited Cardiovascular Disease, Stanford University RCV000035433 SCV000280222 uncertain significance not specified 2013-01-21 no assertion criteria provided clinical testing Note this variant was found in clinical genetic testing performed by one or more labs who may also submit to ClinVar. Thus any internal case data may overlap with the internal case data of other labs. The interpretation reviewed below is that of the Stanford Center for Inherited Cardiovascular Disease

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