ClinVar Miner

Submissions for variant NM_000256.3(MYBPC3):c.646G>A (p.Ala216Thr) (rs201098973)

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Total submissions: 8
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000621185 SCV000736916 uncertain significance Cardiovascular phenotype 2017-09-19 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient or conflicting evidence
CSER_CC_NCGL; University of Washington Medical Center RCV000148666 SCV000190390 uncertain significance Primary familial hypertrophic cardiomyopathy 2014-06-01 criteria provided, single submitter research Low GERP score may suggest that this variant may belong in a lower pathogenicity class
Color RCV000771261 SCV000903376 benign Cardiomyopathy 2018-04-07 criteria provided, single submitter clinical testing
GeneDx RCV000035655 SCV000208235 likely benign not specified 2017-09-21 criteria provided, single submitter clinical testing This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease.
Integrated Genetics/Laboratory Corporation of America RCV000585965 SCV000696333 uncertain significance not provided 2016-06-20 criteria provided, single submitter clinical testing Variant summary: The MYBPC3 c.646G>A (p.Ala216Thr) variant involves the alteration of a non-conserved nucleotide and results in a replacement of a small size and hydrophobic Alanine (A) with a medium size and polar Threonine (T). 3/4 in silico tools predict a benign outcome (SNPs&GO not captured due to low reliability index) for this substitution. This variant was found in 40/109650 control chromosomes, predominantly observed in the African subpopulation at a frequency of 0.0026016 (21/8072). This frequency is about 3 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. The variant was reported in several HCM patients, however, without strong evidence for pathogenicity such as co-segregation information. Importantly, one patient was shown to carry a pathogenic MYBPC3 variant in addition to the variant of interest indicating the p.Ala216Thr variant to be in the neutral spectrum. Moreover, Ala216 is not a conserved residue, several species carry Thr at this position further supporting a benign impact. Clinical diagnostic laboratories classified this variant as VUS/Likely benign. Considering all evidence, the variant was classified as a VUS-possibly benign until more information becomes available.
Invitae RCV000228233 SCV000284249 likely benign Hypertrophic cardiomyopathy 2017-11-06 criteria provided, single submitter clinical testing
Laboratory for Molecular Medicine,Partners HealthCare Personalized Medicine RCV000035655 SCV000059306 likely benign not specified 2016-08-22 criteria provided, single submitter clinical testing
Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease,Montreal Heart Institute RCV000148666 SCV000747990 uncertain significance Primary familial hypertrophic cardiomyopathy 2016-12-20 criteria provided, single submitter clinical testing

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