ClinVar Miner

Submissions for variant NM_000071.2(CBS):c.1224-2A>C (rs375846341)

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Total submissions: 10
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
EGL Genetic Diagnostics,Eurofins Clinical Diagnostics RCV000198380 SCV000225996 pathogenic not provided 2015-06-02 criteria provided, single submitter clinical testing
GeneDx RCV000198380 SCV000249712 pathogenic not provided 2016-09-12 criteria provided, single submitter clinical testing The c.1224-2 A>C splice site variant in the CBS gene was found on approximately 14% of mutant alleles from Central Europe and may represent a founder mutation in this population (Linnebank et al., 2004). This variant destroys the canonical splice acceptor site in intron 13, and is expected to cause abnormal gene splicing. Patients homozygous for c.1224-2 A>C have been reported as non-responsive to vitamin B6 (Linnebank et al., 2004). .
Integrated Genetics/Laboratory Corporation of America RCV000590542 SCV000695302 pathogenic Homocystinuria 2017-03-27 criteria provided, single submitter clinical testing Variant summary: The CBS c.1224-2A>C variant (alternatively also known as IVS11-2A>C) involves the alteration of a highly conserved intronic nucleotide in the canonical splice acceptor site in intron 13, and is expected to cause aberrant gene splicing. 5/5 splice prediction tools also predict abrogation of the splice acceptor site. Consistent to these predictions, this variant is shown to cause exon skipping resulting in an in-frame deletion of exon 12 (amino acids W408 to G453) (Kozick_1992); exon 12 is involved in encoding the CBS domain of the protein (InterPro). In addition, expression of this variant in bacterial (E. coli) system shows that this variant not only leads to abrogation of catalytic activity, but also non-responsiveness to chaperones used to treat the CBS deficiency (Orendac _2004, Kopecka_2011). This variant was found in 7/45474 control chromosomes from ExAC at a frequency of 0.0001539, which does not exceed the estimated maximal expected allele frequency of a pathogenic CBS variant (0.0030414). This variant has been reported in several patients with CBS deficiency in homozygous as well as compound heterozygous with other pathogenic or potentially pathogenic variants including evidence of cosegregation with disease. It is predominantly found in patients from Central Europe, where it has been found on in average 14% of mutant alleles with evidence of founder effect (Linnebank_2004). Available patient and functional data indicate that this variant is likely a severe mutation. Multiple clinical diagnostic laboratories/reputable databases have classified this variant as pathogenic. Taken together, this variant is classified as Pathogenic.
Invitae RCV000174658 SCV000831766 pathogenic Classic homocystinuria 2019-12-26 criteria provided, single submitter clinical testing This sequence change affects an acceptor splice site in intron 13 of the CBS gene. It is expected to disrupt RNA splicing and likely results in an absent or disrupted protein product. This variant is present in population databases (rs375846341, ExAC 0.03%). This variant has been observed to be homozygous or in combination with another CBS variant in individuals affected with homocystinuria (PMID: 11359213, 1301198, 15365998, 20567906), and has been shown to segregate with disease in a family (PMID: 15146473). This variant is also known as IVS11-2A>C or p.W409_G453del in the literature. This variant is described as a founder mutation of European ancestry (PMID: 15365998). ClinVar contains an entry for this variant (Variation ID: 128). Experimental studies have shown that this splicing change causes a deletion of exon 14 and disrupts CBS activity (PMID: 1301198, 20490928, 20506325). For these reasons, this variant has been classified as Pathogenic.
Fulgent Genetics,Fulgent Genetics RCV000174658 SCV000893551 pathogenic Classic homocystinuria 2018-10-31 criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,Illumina RCV000174658 SCV000914972 pathogenic Classic homocystinuria 2018-09-21 criteria provided, single submitter clinical testing The CBS c.1224-2A>C variant, which occurs in a canonical splice acceptor site, has been reported in seven studies and is found in a total of 33 individuals with homocystinuria, including three homozygotes, 28 compound heterozygotes, and two heterozygotes (Kozich et al. 1992; Janosik et al. 2001; Orendae et al. 2004; Linnebank et al. 2004; Magner et al. 2011; Karaca et al. 2014; Alcaide et al. 2015). Control data are unavailable for this variant, which is reported at a frequency of 0.0003 in the European (non-Finnish) population of the Exome Aggregation Consortium. The c.1224-2A>C variant was found to cause an in-frame deletion of exon 12 and result in an inactive protein (Kozich et al. 1992). Functional studies in E. coli confirmed that the c.1224-2A>C variant results in an inactive enzyme (Janosik et al. 2001; Orendae et al. 2004), and CBS activity in cultured skin fibroblasts from probands carrying this variant was significantly reduced compared to wild type (Janosik et al. 2001). Based on the collective evidence and the potential impact of splice acceptor variants, the c.1224-2A>C variant is classified as pathogenic for homocystinuria. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population.
Myriad Women's Health, Inc. RCV000174658 SCV001194127 pathogenic Classic homocystinuria 2019-12-26 criteria provided, single submitter clinical testing NM_000071.2(CBS):c.1224-2A>C is classified as pathogenic in the context of CBS-related homocystinuria. Sources cited for classification include the following: PMID 1301198, 9232191, 11359213, 15146473, 15365998, 20490928 and 20506325. Classification of NM_000071.2(CBS):c.1224-2A>C is based on the following criteria: The variant is located at a canonical splice site, is expected to disrupt gene function and is reported in individuals with the relevant phenotype. Please note: this variant was assessed in the context of healthy population screening.
Centre for Mendelian Genomics,University Medical Centre Ljubljana RCV001196753 SCV001367386 pathogenic Hiatal hernia; Inguinal hernia; Gingival bleeding; Colonic diverticula; Hypomineralization of enamel; Skin nodule 2019-10-24 criteria provided, single submitter clinical testing This variant was classified as: Uncertain significance. The available evidence on this varinat's pathogenicity is insufficient or conflicting. The following ACMG criteria were applied in classifying this variant: PM2,PP3. This variant was detected in hemizygous state.
OMIM RCV000000151 SCV000020294 pathogenic Homocystinuria, pyridoxine-responsive 1992-01-01 no assertion criteria provided literature only
Child Health and Human Development Program,Research Institute of the McGill University Health Center RCV000174658 SCV001424582 pathogenic Classic homocystinuria no assertion criteria provided clinical testing The IVS11-2 A>C (also c.1224-2A>C) was identified in two patients of Eastern European origin in compound heterozygote with c.833C>T (I278T) in one of the patients and c.430G>C (E144Q) in the other. Clinical characteristics in both patients included lens dislocation and elevated fasting homocysteine. Patients had no intellectual impairment and do not respond to treatment with vitamin B6.

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