ClinVar Genomic variation as it relates to human health

Variant classified as Uncertain Significance - Favor Pathogenic. The p.Gln208His variant in MYBPC3 has been previously identified by our laboratory in 3 individ uals with HCM. One of these individuals carried an additional disease-causing va riant, and had an earlier age of onset than an affected parent, suggesting that the p.Gln208His variant may modify severity or independently cause disease. It has also been identified in 17/62206 European chromosomes by the Exome Aggregati on Consortium (ExAC, http://exac.broadinstitute.org; dbSNP rs202139499). This va riant was predicted to be benign using a computational tool clinically validated by our laboratory. This tool's benign prediction is estimated to be correct 89% of the time (Jordan 2011). In summary, while there is some suspicion for a path ogenic role, the clinical significance of the p.Gln208His variant is uncertain.

This variant is associated with the following publications: (PMID: 24033266, 21415409, 23299917, 23861362, 27153395, 27884173, 25637381, 22958901, 25558701, 28518168, 31513939)

Variant summary: MYBPC3 c.624G>C (p.Gln208His) results in a non-conservative amino acid change located in the Immunoglobulin-like domain (IPR003599) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00023 in 243714 control chromosomes, predominantly at a frequency of 0.0044 within the Ashkenazi Jewish subpopulation in the gnomAD database. The observed variant frequency within Ashkenazi Jewish control individuals in the gnomAD database is approximately 4.4 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 Ashkenazi Jewish origin. In addition, the variant has been reported in a Saudi Arabian cohort of individuals who lacked the reported phenotype with an allele frequency of ~0.03, including 1 homozygote (Abouelhoda_2016). The following publication have been ascertained in the context of this evaluation (PMID: 27884173). 12 submissions have been provided as clinical-significance assessments for this variant in ClinVar after 2014, mostly without evidence for independent evaluation, reporting the variant as VUS (n=6) or likely benign (n=6). Based on the evidence outlined above, the variant was classified as likely benign.

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). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.

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). No publications were found based on this search. Allele frequency data from public databases allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign.

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, 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.

Note this variant was found in clinical genetic testing performed by one or more labs who may also submit to ClinVar. Thus any internal case data may overlap with the internal case data of other labs. The interpretation reviewed below is that of the Stanford Center for Inherited Cardiovascular Disease. MYBPC3 p.Gln208His Given the weak case data and the presence in the general population (both reviewed below), we also consider it a variant of unknown significance. I found two unpublished online reports (and no published reports) of the variant in patients with HCM. The variant is listed in the Seidman's online database (http://genepath.med.harvard.edu/~seidman/outdated-mutdb/muts/MYBPC3_Gln208His.html). It appears that they observed this in their cohort, though that is not completely clear and no details are provided. I also found a presentation online by Arad et al that suggests they observed the variant in their Jewish cohort (http://www.his-files.com/pdf/annual2013/presentations/1720_Michael_Arad_schwartz.pdf). The patient also had a TNNI3 variant. In silico analysis with PolyPhen-2 predicts the variant to be probably damaging (with a score of 1.0); the Grantham score is 24. The glutamine at codon 624 is conserved across species. In total the variant has been reported in 6 of 7243 individuals from publicly available population datasets with ~0.1% of Caucasians carrying the variant. The variant was reported online in 5 of 4219 Caucasian individuals and 0 of 2112 African-American individuals in the NHLBI Exome Sequencing Project dataset (as of January 3rd, 2014). The phenotype of those individuals is not publicly available, however the cohorts that were merged to create this dataset were all either general population samples or samples recruited for common cardiovascular disease such as hypertension. Note that other variants with strong evidence for pathogenicity have been seen at similar frequencies in this dataset so this does not necessarily rule out pathogenicity (Pan et al 2012). The variant was observed in 1 in 912 individuals in the NIH ClinSeq cohort (Ng et al 2013). The variant is listed in dbSNP (rs202139499) with entries for the ESP and ClinSeq data as well as a submission from LMM.