Submissions for variant NM_000071.3(CBS):c.667-14_667-7del

dbSNP: rs764160782

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Counsyl	RCV000169271	SCV000220572	likely pathogenic	Classic homocystinuria	2014-08-01	criteria provided, single submitter	literature only
GeneDx	RCV000274429	SCV000329209	pathogenic	not provided	2020-01-23	criteria provided, single submitter	clinical testing	Functional analysis found that c.667-14_667-7delCTCTTTCT results in exon 6 skipping and produces a frameshift (Cozar et al., 2011).; Not observed at a significant frequency in large population cohorts (Lek et al., 2016); In silico analysis, which includes splice predictors and evolutionary conservation, supports a deleterious effect; This variant is associated with the following publications: (PMID: 21520339)
Labcorp Genetics (formerly Invitae), Labcorp	RCV002228777	SCV000769931	pathogenic	HYPERHOMOCYSTEINEMIA, THROMBOTIC, CBS-RELATED	2023-10-23	criteria provided, single submitter	clinical testing	This sequence change falls in intron 7 of the CBS gene. It does not directly change the encoded amino acid sequence of the CBS protein. It affects a nucleotide within the consensus splice site. This variant is present in population databases (rs764160782, gnomAD 0.002%). This variant has been observed in individual(s) with homocystinuria (PMID: 21520339, 28980096; Invitae). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 188911). Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Studies have shown that this variant alters mRNA splicing and is expected to lead to the loss of protein expression (PMID: 21520339). For these reasons, this variant has been classified as Pathogenic.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000780083	SCV000917109	pathogenic	Homocystinuria	2021-11-26	criteria provided, single submitter	clinical testing	Variant summary: CBS c.667-14_667-7delCTCTTTCT alters a nucleotide located close to a canonical splice site and therefore could affect mRNA splicing, leading to a significantly altered protein sequence. Several computational tools predict a significant impact on normal splicing: one predicts the variant abolishes a 3 prime acceptor site, while two predict the variant weakens a 3 prime acceptor site. At least one publication reports experimental evidence that this variant affects mRNA splicing, demonstrating exon 6 skipping in a minigene assay that would produce a frameshift (Cozar 2011). This variant was named using the reference sequence NG_008938.1; cDNA, ENST00000352178 in this report. The variant allele was found at a frequency of 7.2e-06 in 277014 control chromosomes (gnomAD). c.667-14_667-7delCTCTTTCT has been reported in the literature in two compound heterozygous siblings, who were affected with severe Homocystinuria (Cozar 2011). The variant has been also reported in other patients who also carried pathogenic CBS variants (Lorenzini 2018, Asamoah_2021). These data indicate that the variant is likely to be associated with disease. Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. Both laboratories classified the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Fulgent Genetics, Fulgent Genetics	RCV000169271	SCV002796787	likely pathogenic	Classic homocystinuria	2021-10-29	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV000169271	SCV004215532	likely pathogenic	Classic homocystinuria	2024-01-01	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV004821988	SCV005545929	likely pathogenic	Familial thoracic aortic aneurysm and aortic dissection	2024-10-19	criteria provided, single submitter	clinical testing	The c.667-14_667-7delCTCTTTCT intronic variant, located in intron 5 of the CBS gene, results from a deletion of 8 nucleotides within intron 5 of the CBS gene. This variant has been identified in conjunction with other CBS variant(s) in individual(s) with features consistent with homocystinuria, and in at least one instance, the variants were identified in trans (Cozar M et al. Hum Mutat, 2011 Jul;32:835-42; Lorenzini M et al. J Inherit Metab Dis, 2018 Jan;41:109-115; Asamoah A et al. Int J Neonatal Screen, 2021 Jul;7:[ePub ahead of print]). In a minigene assay, this variant showed complete aberrant splicing that resulted in exon skipping with an out-of-frame transcript (Cozar M et al. Hum Mutat, 2011 Jul;32:835-42). This nucleotide positions are not well conserved in available vertebrate species. This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). Based on the majority of available evidence to date, this variant is likely to be pathogenic.