Total submissions: 12
Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
---|---|---|---|---|---|---|---|---|
Laboratory for Molecular 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). |
Gene |
RCV000721104 | SCV000208111 | likely benign | not provided | 2021-02-16 | criteria provided, single submitter | clinical testing | This variant is associated with the following publications: (PMID: 22763267, 26914223) |
Invitae | RCV001087004 | SCV000558160 | benign | Hypertrophic cardiomyopathy | 2024-01-24 | criteria provided, single submitter | clinical testing | |
Ambry Genetics | RCV000619664 | SCV000740205 | likely benign | Cardiovascular phenotype | 2018-11-27 | criteria provided, single submitter | clinical testing | This alteration is classified as likely benign based on a combination of the following: population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. |
Center for Advanced Laboratory Medicine, |
RCV000852651 | SCV000995356 | likely benign | Long QT syndrome; Hypertrophic cardiomyopathy | 2018-06-05 | criteria provided, single submitter | clinical testing | |
Illumina Laboratory Services, |
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 Laboratory Services, |
RCV001106089 | SCV001263122 | likely benign | 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 Diagnostics, |
RCV001177072 | SCV001341201 | likely benign | Cardiomyopathy | 2018-11-14 | criteria provided, single submitter | clinical testing | |
ARUP Laboratories, |
RCV000721104 | SCV002047716 | likely benign | not provided | 2023-09-20 | criteria provided, single submitter | clinical testing | |
Women's Health and Genetics/Laboratory Corporation of America, |
RCV000035515 | SCV002074310 | benign | not specified | 2022-01-17 | criteria provided, single submitter | clinical testing | Variant summary: MYBPC3 c.2614G>A (p.Glu872Lys) results in a conservative amino acid change located in the Fibronectin type III domain (IPR003961) of the encoded protein sequence. Two of four in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.00054 in 173718 control chromosomes, predominantly at a frequency of 0.0037 within the Latino subpopulation in the gnomAD database, including 4 homozygotes. The observed variant frequency within Latino control individuals in the gnomAD database is approximately 4 fold of the estimated maximal expected allele frequency for a pathogenic variant in MYBPC3 causing Cardiomyopathy phenotype (0.001), strongly suggesting that the variant is a benign polymorphism found primarily in populations of Latino origin. c.2614G>A has been reported in the literature in individuals affected with Cardiomyopathy, without strong evidence for causality (Bursetein_2021, Murphy_2016). Co-occurrences with other pathogenic variants have been reported (MYBPC3 c.3811C>T, p.R1271* - internal testing; LMOD2 c.1193G>A, p.W398* Bursetein_2021), providing supporting evidence for a benign role. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Ten clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 and classified the variant as benign(n=2) and likely benign (n=8). Based on the evidence outlined above, the variant was classified as benign. |
Prevention |
RCV003904901 | SCV004718889 | likely benign | MYBPC3-related condition | 2019-06-14 | criteria provided, single submitter | clinical testing | This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). |
Stanford Center for Inherited Cardiovascular Disease, |
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. |