ClinVar Miner

Submissions for variant NM_000256.3(MYBPC3):c.1544A>G (p.Asn515Ser) (rs181834806)

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Total submissions: 9
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000151126 SCV000052947 likely benign not specified 2021-07-06 criteria provided, single submitter clinical testing Variant summary: MYBPC3 c.1544A>G (p.Asn515Ser) results in a conservative amino acid change located in the Immunoglobulin subtype 2 domain (IPR003598) of the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. Consistently, a recent study evaluating the impact of this variant on protein destabilization as estimated by a software that estimates changes in free energy upon mutation from emperically and statistically derived energy functions (FoldX), reported a non-pathogenic outcome (Suay-Corredara_2021). The variant allele was found at a frequency of 0.0001 in 250110 control chromosomes, predominantly at a frequency of 0.0015 within the African or African-American subpopulation in the gnomAD database. The observed variant frequency within African or African-American control individuals in the gnomAD database is approximately 1.5 fold of the estimated maximal expected allele frequency for a pathogenic variant in MYBPC3 causing Hypertrophic Cardiomyopathy phenotype (0.001), strongly suggesting that the variant is a benign polymorphism found primarily in populations of African or African-American origin. c.1544A>G has been reported in the literature in individuals who did not meet the diagnostic criteria for Hypertrophic Cardiomyopathy (example Bick_2012) and as a VUS in settings of multigene panel testing in cohorts of patients with dilated cardiomyopathy (DCM) (example, Verdonschot_2020). These report(s) do not provide unequivocal conclusions about association of the variant with Hypertrophic Cardiomyopathy. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Six clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. Multiple laboratories reported the variant with conflicting assessments (likely benign, n=3, VUS, n=3). Based on the evidence outlined above, the variant was classified as likely benign.
Laboratory for Molecular Medicine, Partners HealthCare Personalized Medicine RCV000151126 SCV000198903 uncertain significance not specified 2012-07-17 criteria provided, single submitter clinical testing The Asn515Ser variant in MYBPC3 has been identified in 3/4338 African American c hromosomes from a broad population by the NHLBI Exome Sequencing Project (http:/ /evs.gs.washington.edu/EVS; dbSNP rs181834806). This frequency is too low to rul e out a role in disease. Our laboratory has detected this variant in 3 individua ls (1 adult individual with HCM and 2 individuals with early onset HCM or HCM + additional congenital heart defects). Of these, 2 individuals were of Black ance stry, which is consistent with the above results by the NHLBI Exome Sequencing P roject (see above). Computational analyses (biochemical amino acid properties, c onservation, AlignGVGD, PolyPhen2, and SIFT) do not provide strong support for o r against an impact to the protein. However, asparagine (Asn) at position 515 is highly conserved across evolutionarily distant species, increasing the likeliho od that an amino acid change would not be tolerated. In summary, additional info rmation is needed to fully assess the clinical significance of this variant.
GeneDx RCV001719700 SCV000207986 likely benign not provided 2019-10-25 criteria provided, single submitter clinical testing This variant is associated with the following publications: (PMID: 22763267, 22958901, 24510615, 32880476)
Invitae RCV000469629 SCV000558164 likely benign Hypertrophic cardiomyopathy 2020-09-17 criteria provided, single submitter clinical testing
Ambry Genetics RCV000617682 SCV000736702 uncertain significance Cardiovascular phenotype 2020-08-21 criteria provided, single submitter clinical testing The p.N515S variant (also known as c.1544A>G), located in coding exon 17 of the MYBPC3 gene, results from an A to G substitution at nucleotide position 1544. The asparagine at codon 515 is replaced by serine, an amino acid with highly similar properties. This variant has been seen in apparently healthy study cohorts, but detailed cardiovascular history was not provided (Kapplinger JD et al. J Cardiovasc Transl Res, 2014 Apr;7:347-61; Golbus JR et al. Circ Cardiovasc Genet, 2012 Aug;5:391-9); the variant was also seen in three individuals in the Framingham and Jackson Heart Study cohorts with very limited cardiovascular findings described (Bick AG et al. Am. J. Hum. Genet., 2012 Sep;91:513-9). 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.
Equipe Genetique des Anomalies du Developpement, Université de Bourgogne RCV000755680 SCV000883089 uncertain significance Left ventricular noncompaction 10 2018-11-21 criteria provided, single submitter clinical testing
Color Health, Inc RCV000777739 SCV000913699 likely benign Cardiomyopathy 2018-10-20 criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,Illumina RCV000755680 SCV001259956 likely benign Left ventricular noncompaction 10 2019-01-21 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 allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign.
Illumina Clinical Services Laboratory,Illumina RCV001103227 SCV001259957 likely benign Familial hypertrophic cardiomyopathy 4 2019-01-21 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. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to determine this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign.

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