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

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000200823	SCV000249676	pathogenic	not provided	2016-09-16	criteria provided, single submitter	clinical testing	p.Ala114Val (A114V) (GCG>GTG): c.341 C>T in exon 5 of the CBS gene (NM_000071.2). The A114V mutation in the CBS gene has been reported in at least 4 individuals in association with homocystinuria (Kozich et al.,1993; Sebastio et al., 1995). The A114V mutation is a conservative amino acid substitution, as these residues share similar properties, and are least likely to impact secondary structure. However, functional studies have shown A114V leads to protein misfolding and instability compared to wild-type alleles (Kozich et al., 2010; Hznida et al., 2012). Additionally, mutations in nearby residues (C109R, G116R) have been reported in association with homocystinuria, further supporting the functional importance of this region of the protein. Finally, the A114V mutation was not observed with any significant frequency in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project or with any significant frequency in the 1000 Genomes Project (McVean et al., 2012). In summary, A114V in the CBS gene is interpreted as a disease-causing mutation. This variant was found in TAADV2-PANCARD,TAAD,TAADV2-1
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
Integrated Genetics/Laboratory Corporation of America	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	2019-12-27	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	RCV001198945	SCV001369940	pathogenic	Status epilepticus; Global developmental delay; Seizures; Overgrowth; Hypomelanotic macule; Perivascular spaces	2019-08-16	criteria provided, single submitter	clinical testing	This variant was classified as: Uncertain significance. The available evidence on this varinat's pathogenicity is insufficient or conflicting. The following ACMG criteria were applied in classifying this variant: PP3. This variant was detected in heterozygous state.
OMIM	RCV000000140	SCV000020283	pathogenic	Homocystinuria, pyridoxine-responsive	1993-06-01	no assertion criteria provided	literature only