ClinVar Miner

Submissions for variant NM_000071.2(CBS):c.1145+7C>T (rs201158177)

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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000174216 SCV000167570 benign not specified 2013-03-28 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.
EGL Genetic Diagnostics,Eurofins Clinical Diagnostics RCV000174216 SCV000225479 benign not specified 2014-11-20 criteria provided, single submitter clinical testing
Invitae RCV000206277 SCV000261852 benign Classic homocystinuria 2019-12-31 criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,Illumina RCV000206277 SCV000436210 likely benign Classic homocystinuria 2018-01-13 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.
ARUP Laboratories, Molecular Genetics and Genomics,ARUP Laboratories RCV000174216 SCV000602920 benign not specified 2019-02-20 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000174216 SCV001338599 benign not specified 2020-04-20 criteria provided, single submitter clinical testing Variant summary: CBS c.1145+7C>T alters a non-conserved nucleotide located close to a canonical splice site and therefore could affect mRNA splicing, leading to a significantly altered protein sequence. 4/4 computational tools predict no significant impact on normal splicing. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 0.0061 in 249694 control chromosomes, predominantly at a frequency of 0.007 within the Non-Finnish European subpopulation in the gnomAD database, including 5 homozygotes. The observed variant frequency within Non-Finnish European control individuals in the gnomAD database is approximately 2 fold of the estimated maximal expected allele frequency for a pathogenic variant in CBS causing Homocystinuria phenotype (0.003), strongly suggesting that the variant is a benign polymorphism found primarily in populations of Non-Finnish European origin. c.1145+7C>T has been reported in the literature (Wesolowska-Andersen_2015). To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Three ClinVar submitters (evaluation after 2014) cite the variant as benign/likely benign. Based on the evidence outlined above, the variant was classified as benign.

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