Submissions for variant NM_000071.2(CBS):c.341C>T (p.Ala114Val) (rs121964964)

Total submissions: 13

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000200823	SCV000249676	likely pathogenic	not provided	2020-10-20	criteria provided, single submitter	clinical testing	Reported in association with homocystinuria (Kozich et al., 1993; Sebastio et al., 1995; de Franchis et al., 1999; Kraus, et al., 1994; Meier et al., 2003; Moat et al., 2004; Katsushima et al., 2006; Urreizti et al., 2006; Pey et al., 2013); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; Published functional studies have shown A114V leads to protein misfolding and instability compared to wild-type alleles (Kozich et al., 2010; Hznida et al., 2012); This variant is associated with the following publications: (PMID: 22612060, 7967489, 22267502, 22985361, 11359213, 25331909, 22069143, 20308073, 14722927, 10408774, 8353501, 28097321, 25087612, 12686134, 20506325, 20490928, 11748855, 20066033, 16307898, 16479318, 7762555, 31589614)
Soonchunhyang University Bucheon Hospital,Soonchunhyang University Medical Center	RCV000490533	SCV000267240	likely pathogenic	Classic homocystinuria	2016-03-18	criteria provided, single submitter	reference population
Counsyl	RCV000490533	SCV000678069	likely pathogenic	Classic homocystinuria	2017-03-01	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000590659	SCV000695305	pathogenic	Homocystinuria	2016-01-26	criteria provided, single submitter	clinical testing	Variant summary: The c.341C>T in CBS gene is a missense variant that involves a highly conserved nucleotide and 4/5 in silico tools predict deleterious outcome. The variant was observed in the large and broad cohorts of the ExAC ans ESP projects at an allele frequency of 0.027%. This frequency does not exceed the maximal expected allele frequency for a pathogenic variant in CBS (0.3%).suggesting this variant is not a common polymorphism. The variant has been reported in several affected individuals presented with features suggestive of Cystathionine--synthase deficiency. Functional studies performed in bacteria-based system showed slight misfolding of the recombinant protein and low enzymatic activity. The variant of interest has been reported as Pathogenic by several reputable databases/diagnostic centers.Taking together, the variant was classified as Pathogenic.
Genomic Research Center,Shahid Beheshti University of Medical Sciences	RCV000490533	SCV000746328	pathogenic	Classic homocystinuria	2017-12-03	criteria provided, single submitter	clinical testing
Fulgent Genetics,Fulgent Genetics	RCV000490533	SCV000893556	pathogenic	Classic homocystinuria	2018-10-31	criteria provided, single submitter	clinical testing
Invitae	RCV000490533	SCV000956328	pathogenic	Classic homocystinuria	2020-10-28	criteria provided, single submitter	clinical testing	This sequence change replaces alanine with valine at codon 114 of the CBS protein (p.Ala114Val). The alanine residue is moderately conserved and there is a small physicochemical difference between alanine and valine. This variant is present in population databases (rs121964964, ExAC 0.03%). This variant has been observed in an individual with low cystathionine- beta synthase enzyme activity, findings that are highly specific for homocystinuria due to cystathionine-beta synthase (CBS) deficiency (PMID: 8353501). It has also been reported in individuals with a clinical diagnosis of cystathionine-beta synthase deficiency (PMID: 7762555) ClinVar contains an entry for this variant (Variation ID: 119). Experimental studies have shown that this missense change disrupts CBS protein activity (PMID: 20490928, 22612060, 22267502, 22069143, 20506325). For these reasons, this variant has been classified as Pathogenic.
Centre for Mendelian Genomics,University Medical Centre Ljubljana	RCV000490533	SCV001369940	pathogenic	Classic homocystinuria	2019-08-16	criteria provided, single submitter	clinical testing	This variant was classified as: Pathogenic. The following ACMG criteria were applied in classifying this variant: PS1,PS3,PM2,PM5.
Institute of Human Genetics, University of Leipzig Medical Center	RCV000490533	SCV001443030	pathogenic	Classic homocystinuria	2020-03-01	criteria provided, single submitter	clinical testing	Review of the variants reported in Reuter et al., 2017, PMID: 28097321: PS3,PS4_moderate,PM2,PM3,PP3
Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen	RCV000200823	SCV001448148	pathogenic	not provided	2020-10-23	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV000490533	SCV001524388	likely pathogenic	Classic homocystinuria	2020-09-11	criteria provided, single submitter	clinical testing	This variant was determined to be likely pathogenic according to ACMG Guidelines, 2015 [PMID:25741868].
Mayo Clinic Laboratories, Mayo Clinic	RCV000200823	SCV001713878	pathogenic	not provided	2020-05-21	criteria provided, single submitter	clinical testing	PS3, PS4_moderate, PM3_verystrong, PP3, PP4
OMIM	RCV000000140	SCV000020283	pathogenic	Homocystinuria, pyridoxine-responsive	1993-06-01	no assertion criteria provided	literature only