ClinVar Miner

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

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Total submissions: 9
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
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).
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 RCV001087004 SCV000558160 benign Hypertrophic cardiomyopathy 2019-12-31 criteria provided, single submitter clinical testing
Ambry Genetics RCV000619664 SCV000740205 likely benign Cardiovascular phenotype 2018-11-27 criteria provided, single submitter clinical testing Subpopulation frequency in support of benign classification;Other data supporting benign classification
Center for Advanced Laboratory Medicine, UC San Diego Health,University of California San Diego RCV000852651 SCV000995356 likely benign Long QT syndrome; Hypertrophic cardiomyopathy 2018-06-05 criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,Illumina RCV001106088 SCV001263121 benign Left ventricular noncompaction 10 2018-01-12 criteria provided, single submitter clinical testing This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease.
Illumina Clinical Services Laboratory,Illumina RCV001106089 SCV001263122 likely benign Familial hypertrophic cardiomyopathy 4 2018-01-12 criteria provided, single submitter clinical testing This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease.
Color RCV001177072 SCV001341201 likely benign Cardiomyopathy 2018-11-14 criteria provided, single submitter clinical testing
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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