Submissions for variant NM_000071.3(CBS):c.209+1G>A

dbSNP: rs751464024

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000780080	SCV000917106	pathogenic	Homocystinuria	2018-09-10	criteria provided, single submitter	clinical testing	Variant summary: CBS c.209+1G>A is located in a canonical splice-site and is predicted to affect mRNA splicing resulting in a significantly altered protein due to either exon skipping, shortening, or inclusion of intronic material. Several computational tools predict a significant impact on normal splicing: Five predict the variant abolishes a 5' splicing donor site. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 4.1e-06 in 244714 control chromosomes (gnomAD). c.209+1G>A has been reported in the literature in individuals affected with Homocystinuria (Alcaide_2015, Li_2018, Poloni_2017). These data indicate that the variant is likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function. The most pronounced variant effect results in <10% of normal activity. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014. Based on the evidence outlined above, the variant was classified as pathogenic.
Labcorp Genetics (formerly Invitae), Labcorp	RCV002234171	SCV001590392	pathogenic	HYPERHOMOCYSTEINEMIA, THROMBOTIC, CBS-RELATED	2025-01-23	criteria provided, single submitter	clinical testing	This sequence change affects a donor splice site in intron 3 of the CBS gene. It is expected to disrupt RNA splicing. Variants that disrupt the donor or acceptor splice site typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in CBS are known to be pathogenic (PMID: 10338090, 12124992). This variant is present in population databases (rs751464024, gnomAD 0.0009%). Disruption of this splice site has been observed in individual(s) with homocystinuria (PMID: 10215408, 29508359). 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 IVS3+1G>A and IVS1+1G>A. ClinVar contains an entry for this variant (Variation ID: 632738). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic.
GeneDx	RCV001558321	SCV001780243	pathogenic	not provided	2023-03-31	criteria provided, single submitter	clinical testing	Identified in multiple patients with homocystinuria in the published literature (Gordon et al., 1998; Alcaide et al., 2015; Poloni et al., 2018; Li et al., 2018); Canonical splice site variant predicted to result in a null allele in a gene for which loss of function is a known mechanism of disease; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 25525159, 29352562, 10215408, 29508359, 25218699, 12815602, 12124992)
Myriad Genetics, Inc.	RCV001389140	SCV002060056	pathogenic	Classic homocystinuria	2021-11-18	criteria provided, single submitter	clinical testing	NM_000071.2(CBS):c.209+1G>A is a canonical splice variant classified as pathogenic in the context of homocystinuria, CBS-related. c.209+1G>A has been observed in cases with relevant disease (PMID: 12815602, 12124992, 29508359). Functional assessments of this variant are available in the literature (PMID: 29508359). c.209+1G>A has been observed in population frequency databases (gnomAD: NFE <0.001%). In summary, NM_000071.2(CBS):c.209+1G>A is a canonical splice variant in a gene where loss of function is a known mechanism of disease, is predicted to disrupt protein function, and 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.
Revvity Omics, Revvity	RCV001389140	SCV003820584	pathogenic	Classic homocystinuria	2022-03-02	criteria provided, single submitter	clinical testing
PreventionGenetics, part of Exact Sciences	RCV003424337	SCV004117655	likely pathogenic	CBS-related disorder	2023-03-06	criteria provided, single submitter	clinical testing	The CBS c.209+1G>A variant is predicted to disrupt the GT donor site and interfere with normal splicing. This variant has been reported in patients with autosomal recessive CBS-related homocystinuria (Gordon et al. 1997. PubMed ID: 10215408; Li et al. 2018. PubMed ID: 29508359). This variant is reported in 0.00089% of alleles in individuals of European (Non-Finnish) descent in gnomAD (http://gnomad.broadinstitute.org/variant/21-44492094-C-T). Variants that disrupt the consensus splice donor site in CBS are expected to be pathogenic. This variant is interpreted as likely pathogenic.
Baylor Genetics	RCV001389140	SCV004215550	pathogenic	Classic homocystinuria	2023-01-15	criteria provided, single submitter	clinical testing
Natera, Inc.	RCV001389140	SCV002083828	pathogenic	Classic homocystinuria	2020-07-28	no assertion criteria provided	clinical testing