Submissions for variant NM_000071.3(CBS):c.828+1G>A

gnomAD frequency: 0.00001  dbSNP: rs763290176

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Counsyl	RCV000673023	SCV000798187	pathogenic	Classic homocystinuria	2018-02-27	criteria provided, single submitter	clinical testing
Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago	RCV000673023	SCV000898571	likely pathogenic	Classic homocystinuria	2021-11-22	criteria provided, single submitter	clinical testing	CBS NM_000071.2 exon 9 c.828+1G>A: This variant has been reported in the literature as a compound heterozygote in 1 individual with homocystinuria (Kraus 1999 PMID:10338090). This variant is present in 2/110146 European alleles in the Genome Aggregation Database (http://gnomad.broadinstitute.org/rs763290176). Please note, disease causing variants may be present in control databases at low frequencies, reflective of the general population and/or variable expressivity. Evolutionary conservation and computational predictive tools for this variant are limited or unavailable. Of note, this variant alters the consensus splice sequence (+/- 1,2) which is predicted to result in an absent or abnormal protein. Loss of function variants have been reported in association with disease for this gene (Kraus 1999 PMID:10338090). In summary, data on this variant is highly suspicious for disease, but requires further evidence for pathogenicity. Therefore, this variant is classified as likely pathogenic.
Labcorp Genetics (formerly Invitae), Labcorp	RCV002232806	SCV000961094	pathogenic	HYPERHOMOCYSTEINEMIA, THROMBOTIC, CBS-RELATED	2025-01-14	criteria provided, single submitter	clinical testing	This sequence change affects a donor splice site in intron 9 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 (rs763290176, gnomAD 0.002%). Disruption of this splice site has been observed in individuals with homocystinuria (PMID: 15365998, 29352562). This variant is also known as IVS7+1G>A, 8297G>A. ClinVar contains an entry for this variant (Variation ID: 556952). 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.
Centre for Mendelian Genomics, University Medical Centre Ljubljana	RCV000673023	SCV001367349	pathogenic	Classic homocystinuria	2019-08-29	criteria provided, single submitter	clinical testing	This variant was classified as: Pathogenic. The following ACMG criteria were applied in classifying this variant: PVS1,PM2,PP5.
CeGaT Center for Human Genetics Tuebingen	RCV002060827	SCV002496707	pathogenic	not provided	2024-03-01	criteria provided, single submitter	clinical testing	CBS: PM3:Very Strong, PVS1, PM2
GeneDx	RCV002060827	SCV002552697	pathogenic	not provided	2022-07-22	criteria provided, single submitter	clinical testing	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, 16479318, 15365998, 10338090)
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV003226363	SCV003922492	pathogenic	Homocystinuria	2023-03-03	criteria provided, single submitter	clinical testing	Variant summary: CBS c.828+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: Four 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 8.1e-06 in 247508 control chromosomes. c.828+1G>A has been reported in the literature in multiple individuals affected with Homocystinuria, including 1 homozygote (example: Poloni_2017), individuals carrying an additional pathogenic variant (examples: Kraus_1999, Linnebank_2005, Poloni_2017, VanHove_2019) of which 3 reported to segregate in families (examples: Kraus_1999, Linnebank_2005, Poloni_2017). These data indicate that the variant is very likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Eight ClinVar submitters have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic (n=7) or likely pathogenic (n=1). Based on the evidence outlined above, the variant was classified as pathogenic.
Baylor Genetics	RCV000673023	SCV004213845	pathogenic	Classic homocystinuria	2024-01-21	criteria provided, single submitter	clinical testing
Natera, Inc.	RCV000673023	SCV001462119	pathogenic	Classic homocystinuria	2020-09-16	no assertion criteria provided	clinical testing