ClinVar Miner

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

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Total submissions: 10
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Laboratory for Molecular Medicine, Partners HealthCare Personalized Medicine RCV000035655 SCV000059306 likely benign not specified 2016-08-22 criteria provided, single submitter clinical testing proposed classification - variant undergoing re-assessment, contact laboratory
CSER _CC_NCGL, University of Washington 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
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.
Invitae RCV001084987 SCV000284249 likely benign Hypertrophic cardiomyopathy 2019-12-31 criteria provided, single submitter clinical testing
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.
Ambry Genetics RCV000621185 SCV000736916 likely benign Cardiovascular phenotype 2018-08-27 criteria provided, single submitter clinical testing In silico models in agreement (benign);Other data supporting benign classification
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
Color RCV000771261 SCV000903376 benign Cardiomyopathy 2018-04-07 criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,Illumina RCV001106360 SCV001263419 likely benign Familial hypertrophic cardiomyopathy 4 2019-08-14 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.
Illumina Clinical Services Laboratory,Illumina RCV001106361 SCV001263420 likely benign Left ventricular noncompaction 10 2019-08-14 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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