Submissions for variant NM_000071.3(CBS):c.362G>A (p.Arg121His)

gnomAD frequency: 0.00010  dbSNP: rs770095972

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV002228611	SCV001224398	pathogenic	HYPERHOMOCYSTEINEMIA, THROMBOTIC, CBS-RELATED	2023-11-05	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 121 of the CBS protein (p.Arg121His). This variant is present in population databases (rs770095972, gnomAD 0.03%). This missense change has been observed in individuals with homocystinuria (PMID: 10338090, 16307898, 16479318). ClinVar contains an entry for this variant (Variation ID: 188948). 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 with a positive predictive value of 95%. Experimental studies have shown that this missense change affects CBS function (PMID: 16307898, 22267502). This variant disrupts the p.Arg121 amino acid residue in CBS. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 10338090, 16307898, 21520339; Invitae). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001192720	SCV001361015	pathogenic	Homocystinuria	2020-08-31	criteria provided, single submitter	clinical testing	Variant summary: CBS c.362G>A (p.Arg121His) results in a non-conservative amino acid change located in the Pyridoxal-phosphate dependent enzyme domain 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 2.4e-05 in 251070 control chromosomes. c.362G>A has been reported in the literature in multiple individuals affected with Homocystinuria (example, Katsushima_2006, Urreizti_2006, Kraus_1999). These data indicate that the variant is very 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 severely impaired enzyme activity resulting from impaired tetramer assembly (Katsushima_2006). One clinical diagnostic laboratory has submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation and classified the variant as pathogenic citing overlapping evidence utilized in the context of this evaluation. Based on the evidence outlined above, the variant was classified as pathogenic.
Myriad Genetics, Inc.	RCV000169322	SCV002060177	likely pathogenic	Classic homocystinuria	2021-11-03	criteria provided, single submitter	clinical testing	NM_000071.2(CBS):c.362G>A(R121H) is a missense variant classified as likely pathogenic in the context of homocystinuria, CBS-related. R121H has been observed in cases with relevant disease (PMID: 10338090, 16307898, 16479318, 30873612). Functional assessments of this variant are available in the literature (PMID: 16307898, 22267502). R121H has been observed in population frequency databases (gnomAD: AFR 0.02%). In summary, NM_000071.2(CBS):c.362G>A(R121H) is a missense 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.
Ambry Genetics	RCV002453568	SCV002615953	pathogenic	Familial thoracic aortic aneurysm and aortic dissection	2022-06-22	criteria provided, single submitter	clinical testing	The p.R121H pathogenic mutation (also known as c.362G>A), located in coding exon 3 of the CBS gene, results from a G to A substitution at nucleotide position 362. The arginine at codon 121 is replaced by histidine, an amino acid with highly similar properties. This variant has been detected in the homozygous and compound heterozygous states with other alterations in CBS in several individuals with homocystinuria, features of homocystinuria and/or CBS-deficiency (Kraus JP et al. Hum Mutat, 1999;13:362-75; Urreizti R et al. J Hum Genet, 2006 Feb;51:305-313; Katsushima F et al. Mol Genet Metab, 2006 Apr;87:323-8; Van Hove JLK et al. J Inherit Metab Dis, 2019 05;42:424-437). In expression studies in E. coli, this variant showed decreased enzyme activity and impaired capability to correctly form tetramers (Katsushima F et al. Mol Genet Metab, 2006 Apr;87:323-8). In a yeast growth assay, this variant was characterized as nonfunctional (Mayfield JA et al. Genetics, 2012 Apr;190:1309-23). In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation.
Baylor Genetics	RCV000169322	SCV004213844	pathogenic	Classic homocystinuria	2024-02-15	criteria provided, single submitter	clinical testing
Natera, Inc.	RCV000169322	SCV001452099	pathogenic	Classic homocystinuria	2020-09-16	no assertion criteria provided	clinical testing