ClinVar Miner

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

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Total submissions: 7
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Integrated Genetics/Laboratory Corporation of America RCV000151126 SCV000052947 uncertain significance not specified 2017-06-23 criteria provided, single submitter clinical testing Variant summary: The MYBPC3 c.1544A>G (p.Asn515Ser) variant involves the alteration of a conserved nucleotide. 3/4 in silico tools predict a benign outcome for this variant (SNPsandGO not captured due to low reliability index). This variant was found in 18/121484 control chromosomes, predominantly observed in the African subpopulation at a frequency of 0.001734 (17/9804). This frequency is about 2 times the estimated maximal expected allele frequency of a pathogenic MYBPC3 variant (0.0010005), suggesting this is likely a benign polymorphism found primarily in the populations of African origin. In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as VUS(3)/likely benign(1). LMM has reported to detect this variant in 3 individuals (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 ancestry, which is consistent with presence of the variant in individuals of African ancestry in ExAC. Lastly, it was observed among 3 patients in the Jackson Heart Study, none of whom met the clinical diagnostic criteria for HCM based on a left ventricular wall thickness measurement of less than 15mm. Taken together, it is likely that the variant is a rare polymorphism, however, more definitive data are needed to unequivocally rule out causality. Therefore, this variant has been classified as a variant of uncertain significance - possibly 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:/ /; 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 RCV000151126 SCV000207986 uncertain significance not specified 2017-10-04 criteria provided, single submitter clinical testing A variant of uncertain significance has been identified in the MYBPC3 gene. The N515S variant has been previously identified in three African American individuals without HCM in the Jackson Heart Study (Bick et al., 2012). This variant was also reported in one individual from a cohort of 427 ostensibly healthy individuals from various ethnic backgrounds (Kapplinger et al., 2014). However, in both of these studies, follow-up cardiac evaluations were not reported. The N515S variant is observed in 17/9804 (0.17%) alleles from individualS of African ancestry in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). Additionally, N515S is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties. While this substitution occurs at a position that is conserved across species, in silico analysis is inconsistent in its predictions as to whether or not the variant is damaging to the protein structure/function. Lastly, although a missense variant at the same residue (N515D) has been reported in the Human Gene Mutation Database in association with HCM (Stenson et al., 2014), the clinical significance of this variant also remains to be definitively determined.
Invitae RCV000469629 SCV000558164 likely benign not provided 2019-02-28 criteria provided, single submitter clinical testing
Ambry Genetics RCV000617682 SCV000736702 uncertain significance Cardiovascular phenotype 2016-11-03 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient evidence
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 RCV000777739 SCV000913699 likely benign Cardiomyopathy 2018-10-20 criteria provided, single submitter clinical testing

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