Submissions for variant NM_000071.3(CBS):c.1224-2A>C

gnomAD frequency: 0.00008  dbSNP: rs375846341

Total submissions: 17

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Eurofins Ntd Llc (ga)	RCV000198380	SCV000225996	pathogenic	not provided	2015-06-02	criteria provided, single submitter	clinical testing
GeneDx	RCV000198380	SCV000249712	pathogenic	not provided	2023-07-07	criteria provided, single submitter	clinical testing	Segregates with disease in affected individuals from a single family in published literature (Orendae et al., 2004); Published functional studies demonstrate decreases enzyme activity (Kozich et al., 1992; Kopeck et al., 2011; Alcaide et al., 2015); Canonical splice site variant predicted to result in an in-frame loss of the adjacent exon in a gene for which loss of function is a known mechanism of disease; This variant is associated with the following publications: (PMID: 24211323, 21030686, 1301198, 27059523, 20567906, 25525159, 15365998, 20490928, 20506325, 15146473, 11359213, 32232970, 25218699)
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	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.
Labcorp Genetics (formerly Invitae), Labcorp	RCV002227960	SCV000831766	pathogenic	HYPERHOMOCYSTEINEMIA, THROMBOTIC, CBS-RELATED	2023-12-19	criteria provided, single submitter	clinical testing	This sequence change affects an acceptor splice site in intron 13 of the CBS gene. RNA analysis indicates that disruption of this splice site induces altered splicing and likely results in a shortened protein product. This variant is present in population databases (rs375846341, gnomAD 0.1%). Disruption of this splice site has been observed in individual(s) with homocystinuria (PMID: 1301198, 11359213, 15146473, 15365998, 20567906). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. It has also been observed to segregate with disease in related individuals. This variant is also known as IVS11-2A>C or p.W409_G453del. ClinVar contains an entry for this variant (Variation ID: 128). Studies have shown that disruption of this splice site results in skipping of exon 14, but is expected to preserve the integrity of the reading-frame (PMID: 1301198, 20490928, 20506325). For these reasons, this variant has been classified as Pathogenic.
Fulgent Genetics, Fulgent Genetics	RCV000174658	SCV000893551	pathogenic	Classic homocystinuria	2021-08-25	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, 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 Genetics, Inc.	RCV000174658	SCV001194127	pathogenic	Classic homocystinuria	2021-11-09	criteria provided, single submitter	clinical testing	NM_000071.2(CBS):c.1224-2A>C is a canonical splice variant classified as pathogenic in the context of homocystinuria, CBS-related. c.1224-2A>C has been observed in cases with relevant disease (PMID: 15365998). Functional assessments of this variant are available in the literature (PMID: 20506325, 20490928). c.1224-2A>C has been observed in population frequency databases (gnomAD: ASJ 0.14%). In summary, NM_000071.2(CBS):c.1224-2A>C is a canonical splice variant that has been observed more frequently in cases with the relevant disease than in healthy populations. Please note: this variant was assessed in the context of healthy population screening.
Centre for Mendelian Genomics, University Medical Centre Ljubljana	RCV000174658	SCV001367386	pathogenic	Classic homocystinuria	2019-10-24	criteria provided, single submitter	clinical testing	This variant was classified as: Pathogenic. The following ACMG criteria were applied in classifying this variant: PVS1,PS1,PM2.
3billion	RCV000174658	SCV002573357	pathogenic	Classic homocystinuria	2022-09-01	criteria provided, single submitter	clinical testing	The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.008%). This variant on the canonical splice site is predicted to alter splicing, resulting in a loss or disruption of normal protein function. Multiple pathogenic loss-of-function variants are reported downstream of the variant. The variant has been reported at least twice as pathogenic with clinical assertions and evidence for the classification (ClinVar ID: VCV000000128). Therefore, this variant is classified as Pathogenic according to the recommendation of ACMG/AMP guideline.
Ambry Genetics	RCV002354142	SCV002654814	pathogenic	Familial thoracic aortic aneurysm and aortic dissection	2020-11-24	criteria provided, single submitter	clinical testing	The c.1224-2A>C intronic pathogenic mutation results from an A to C substitution two nucleotides upstream from coding exon 12 in the CBS gene. This alteration has been reported with p.I278T in a subject with homocystinuria (Kozich V et al. Hum Mutat, 1992;1:113-23). In silico splice site analysis predicts that this alteration will weaken the native splice acceptor site and will result in the creation or strengthening of a novel splice acceptor site. Alterations that disrupt the canonical splice site are expected to cause aberrant splicing, resulting in an abnormal protein or a transcript that is subject to nonsense-mediated mRNA decay. As such, this alteration is classified as a disease-causing mutation.
CeGaT Center for Human Genetics Tuebingen	RCV000198380	SCV004033912	pathogenic	not provided	2023-07-01	criteria provided, single submitter	clinical testing	CBS: PVS1:Strong, PM2, PM3, PP4, PS3:Supporting
Baylor Genetics	RCV000174658	SCV004213857	pathogenic	Classic homocystinuria	2024-03-29	criteria provided, single submitter	clinical testing
Revvity Omics, Revvity	RCV000174658	SCV004238581	pathogenic	Classic homocystinuria	2023-06-19	criteria provided, single submitter	clinical testing
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.
Natera, Inc.	RCV000174658	SCV001461064	pathogenic	Classic homocystinuria	2020-09-16	no assertion criteria provided	clinical testing
PreventionGenetics, part of Exact Sciences	RCV003944786	SCV004765662	pathogenic	CBS-related disorder	2024-05-16	no assertion criteria provided	clinical testing	The CBS c.1224-2A>C variant is predicted to disrupt the AG splice acceptor site and interfere with normal splicing. This variant has been reported in the homozygous state or with a second CBS variant in individuals with homocystinuria, and has been shown to cause skipping of exon 14 (Kozich et al. 1992. PubMed ID: 1301198; Linnebank et al. 2004. PubMed ID: 15365998; Kopecká et al. 2010. PubMed ID: 20490928). In at least one individual, this variant was shown by family segregation studies to be on the opposite allele as a known pathogenic variant in CBS (Kozich et al. 1992. PubMed ID: 1301198). This variant is reported in 0.14% of alleles in individuals of Ashkenazi Jewish descent in gnomAD. Variants that disrupt the consensus splice acceptor site in CBS are expected to be pathogenic. This variant is interpreted as pathogenic.