ClinVar Miner

Submissions for variant NM_000256.3(MYBPC3):c.2614G>A (p.Glu872Lys) (rs190765116)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000619664 SCV000740205 uncertain significance Cardiovascular phenotype 2017-08-08 criteria provided, single submitter clinical testing
GeneDx RCV000035515 SCV000208111 likely benign not specified 2018-01-30 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 RCV000464124 SCV000558160 benign Hypertrophic cardiomyopathy 2018-01-01 criteria provided, single submitter clinical testing
Laboratory for Molecular Medicine,Partners HealthCare Personalized Medicine RCV000035515 SCV000059165 likely benign not specified 2016-07-18 criteria provided, single submitter clinical testing p.Glu872Lys in exon 26 of MYBPC3: This variant is not expected to have clinical significance because it is not located within the splice consensus sequence. It has been identified in 0.7% (37/5574) of Latino chromosomes, including 2 homozy gotes, by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.org ; dbSNP rs190765116).
Stanford Center for Inherited Cardiovascular Disease,Stanford University RCV000721104 SCV000280241 likely benign not provided 2016-08-22 no assertion criteria provided provider interpretation p.Glu872Lys (E872K; c.2614 G>A) in the MYBPC3 gene. We classify it as a variant of unknown significance. This variant has not previously been reported in individuals with HCM. There is no published segregation data. At SCICD, it has segregated with disease in a brother and sister with HCM. Variation at the following adjacent residue has been reported in the HGMD to be associated with cardiomyopathy: Pro873His, Pro873Leu. This supports the functional importance of this region of the protein. This is a non-conservative amino acid change, resulting in the replacement of a glutamic acid (acidic) with a lysine (basic). Glutamic acid at this location is 100% conserved across 9 mammalian species. The adjacent residues are also highly conserved. In silico analysis with PolyPhen-2 (http://genetics.bwh.harvard.edu/pph2/) predicts the variant to be "Probably Damaging" with a score of 0.993. SIFT predicts it to be deleterious, with a score of 0.01. ExAC data (aug 2016): All: AF: 0.00058673 38/64766 alleles Highest frequency - Latinos: AF: 0.00663796 37/5574 It has been seen in 1 out of ~7240 individuals from publicly available population datasets as of January 24, 2014. More specifically, it was seen in 1 out of 64 individuals of Mexican ancestry in 1000 Genomes, for a MAF in that population of 0.0078 (1/128 alleles). This may argue against pathogenicity, since this is the same ethnicity as our patient. In 1000 Genomes, the overall Minor Allele Frequency (MAF) was 0.0005 (1/2178 alleles). This variant is not listed in the NHLBI Exome Sequencing Project dataset (http://evs.gs.washington.edu/EVS/), which currently includes variant calls on ~4150 Caucasian and ~2000 African American individuals.

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