Submissions for variant NM_000071.3(CBS):c.394C>T (p.Arg132Cys)

gnomAD frequency: 0.00038  dbSNP: rs140002610

Total submissions: 14

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000726351	SCV000249679	uncertain significance	not provided	2021-03-19	criteria provided, single submitter	clinical testing	Has not been previously published as pathogenic or benign to our knowledge; In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; Reported in ClinVar as a variant of uncertain significance (ClinVar Variant ID#212843; Landrum et al., 2016)
Eurofins Ntd Llc (ga)	RCV000726351	SCV000344004	uncertain significance	not provided	2016-08-09	criteria provided, single submitter	clinical testing
Invitae	RCV002517995	SCV000543519	uncertain significance	HYPERHOMOCYSTEINEMIA, THROMBOTIC, CBS-RELATED	2022-11-01	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 132 of the CBS protein (p.Arg132Cys). This variant is present in population databases (rs140002610, gnomAD 0.05%). This variant has not been reported in the literature in individuals affected with CBS-related conditions. ClinVar contains an entry for this variant (Variation ID: 212843). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt CBS protein function. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Ambry Genetics	RCV002315523	SCV000738480	uncertain significance	Familial thoracic aortic aneurysm and aortic dissection	2022-01-05	criteria provided, single submitter	clinical testing	The p.R132C variant (also known as c.394C>T), located in coding exon 3 of the CBS gene, results from a C to T substitution at nucleotide position 394. The arginine at codon 132 is replaced by cysteine, an amino acid with highly dissimilar properties. This amino acid position is well conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Counsyl	RCV000460928	SCV000797533	uncertain significance	Classic homocystinuria	2018-02-05	criteria provided, single submitter	clinical testing
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000726351	SCV000885145	uncertain significance	not provided	2023-06-29	criteria provided, single submitter	clinical testing	The CBS c.394C>T, p.Arg132Cys variant (rs140002610), to our knowledge, is not reported in the medical literature in CBS-related conditions but is reported in ClinVar (Variation ID: 212843). This variant is found in the non-Finnish European population with an allele frequency of 0.05% (67/128912 alleles) in the Genome Aggregation Database. Computational analyses predict that this variant is deleterious (REVEL: 0.75). Due to limited information, the clinical significance of the p.Arg132Cys variant is uncertain at this time.
Illumina Laboratory Services, Illumina	RCV000460928	SCV001298059	uncertain significance	Classic homocystinuria	2017-09-05	criteria provided, single submitter	clinical testing	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	RCV000460928	SCV002557054	uncertain significance	Classic homocystinuria	2022-02-02	criteria provided, single submitter	clinical testing	Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as VUS-3B. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with B6-responsive and nonresponsive types homocystinuria and hyperhomocysteinemic thrombosis (MIM#236200). (I) 0106 - This gene is associated with autosomal recessive disease. (I) 0200 - Variant is predicted to result in a missense amino acid change from arginine to cysteine. (I) 0251 - This variant is likely heterozygous. (I) 0304 - Variant is present in gnomAD (v3) <0.01 for a recessive condition (26 heterozygotes, 8 homozygotes). (SP) 0309 - An alternative amino acid change at the same position has been observed in gnomAD (v2) (3 heterozygotes, 0 homozygotes). (I) 0501 - Missense variant consistently predicted to be damaging by multiple in silico tools or highly conserved with a major amino acid change. (SP) 0600 - Variant is located in the annotated cystathionine beta-synthase domain (NCBI). (I) 0710 - Other missense variants comparable to the one identified in this case have inconclusive previous evidence for pathogenicity. These alternative changes (p.(Arg132His), p.(Arg132Ser)) have been reported as a VUS (ClinVar). (I) 0809 - Previous evidence of pathogenicity for this variant is inconclusive. This variant has been reported many times as a VUS (ClinVar). (I) 0905 - No published segregation evidence has been identified for this variant. (I) 1007 - No published functional evidence has been identified for this variant. (I) 1205 - This variant has been shown to be likely maternally inherited (by trio analysis). (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign
Fulgent Genetics, Fulgent Genetics	RCV000460928	SCV002779289	uncertain significance	Classic homocystinuria	2022-04-12	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV000726351	SCV004153731	likely benign	not provided	2024-03-01	criteria provided, single submitter	clinical testing	CBS: BS2
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV003993881	SCV004814024	uncertain significance	not specified	2024-02-27	criteria provided, single submitter	clinical testing	Variant summary: CBS c.394C>T (p.Arg132Cys) results in a non-conservative amino acid change located in the Tryptophan synthase beta chain-like, PALP domain (IPR001926) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00061 in 1044308 control chromosomes in the gnomAD database, including 89 homozygotes. This frequency is not significantly higher than estimated for a pathogenic variant in CBS causing Homocystinuria (0.00061 vs 0.003), allowing no conclusion about variant significance. To our knowledge, no occurrence of c.394C>T in individuals affected with Homocystinuria and no experimental evidence demonstrating its impact on protein function have been reported. ClinVar contains an entry for this variant (Variation ID: 212843). Based on the evidence outlined above, the variant was classified as VUS-possibly benign.
Centre de Biologie Pathologie Génétique, Centre Hospitalier Universitaire de Lille	RCV001252179	SCV001427929	uncertain significance	Intellectual disability	2019-01-01	no assertion criteria provided	clinical testing
Natera, Inc.	RCV000460928	SCV001452097	uncertain significance	Classic homocystinuria	2020-09-16	no assertion criteria provided	clinical testing
Clinical Genetics Laboratory, University Hospital Schleswig-Holstein	RCV000460928	SCV002029188	uncertain significance	Classic homocystinuria	2021-10-01	no assertion criteria provided	clinical testing