ClinVar Miner

Submissions for variant NM_000071.2(CBS):c.1330G>A (p.Asp444Asn) (rs28934891)

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Total submissions: 10
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Counsyl RCV000174656 SCV000678050 likely pathogenic Homocystinuria due to CBS deficiency 2015-08-28 criteria provided, single submitter clinical testing
EGL Genetic Diagnostics,Eurofins Clinical Diagnostics RCV000078108 SCV000225994 pathogenic not provided 2013-06-20 criteria provided, single submitter clinical testing
Fulgent Genetics RCV000174656 SCV000893550 likely pathogenic Homocystinuria due to CBS deficiency 2018-10-31 criteria provided, single submitter clinical testing
GeneDx RCV000078108 SCV000249732 pathogenic not provided 2018-09-25 criteria provided, single submitter clinical testing The D444N pathogenic variant in the CBS gene has been previously reported in multiple homozygous or compound heterozygous individuals with classical homocystinuria due to cystathione beta-synthase (CBS) deficiency (Kluijtmans et al., 1996; Maclean et al., 2002; De Lucca et al., 2004; Moat et al., 2004; Urreizti et al., 2006; Cozar et al., 2011; Martinez- Gutierrez et al., 2011; Alcaide et al., 2015). Additionally, D444N was not observed at any significant frequency in large population cohorts (Lek et al., 2016). The D444N variant is a semi-conservative amino acid substitution, which may impact secondary protein structure as these residues differ in some properties. This substitution occurs at a position within the C-terminal auto-inhibitory regulatory domain of the CBS enzyme. In-silico analyses, including protein predictors and evolutionary conservation, support a deleterious effect.Study of fibroblasts from a patient homozygous for D444N found enzyme activity in the heterozygous range, despite severely increased homocysteine levels and classic clinical manifestations of homocystinuria (Kluijtmans et al., 1996). Additionally, multiple expression studies have also shown that D444N results in a CBS enzyme with higher than expected residual activity compared to other pathogenic variants in the CBS gene (Mendes et al., 2014a; Mendes et al., 2014b; Alcaide et al., 2015). However, several functional studies have demonstrated that D444N disrupts CBS protein interaction with S-adenosylmethionine (also called SAM or AdoMet), a cofactor needed for CBS allosteric activation and protein stability, thus causing reduced CBS protein levels and impairing its ability to be properly activated by physiological levels of SAM (Kluijtmans et al., 1996; Evande et al., 2002; Scott et al., 2004; Prudova et al., 2006; Mendes et al., 2014a; Mendes et al., 2014b; Alcaide et al., 2015). Thus, D444N, belongs to the class of pathogenic variants in the CBS gene that demonstrate significant residual CBS activity by standard in vitro assays, but impair CBS enzyme function by disruption of proper regulation through SAM activation (Mendes et al., 2014a; Alcaide et al., 2015).
Illumina Clinical Services Laboratory,Illumina RCV000174656 SCV000914970 pathogenic Homocystinuria due to CBS deficiency 2017-09-17 criteria provided, single submitter clinical testing Across a selection of the available literature, the CBS c.1330G>A (p.Asp444Asn) variant has been identified in at least nine individuals with homocystinuria including four in a homozygous state, three in a compound heterozygous state, and two siblings with the variant in a heterozygous state (Kluijtmans et al. 1996; Kelly et al. 2003; Urreizti et al. 2006; Lefaucheur et al. 2008; Cozar et al. 2011). The variant was also identified in a heterozygous state in the unaffected parents and sister of one of the homozygous individuals (Kluijtmans et al. 1996). The compound heterozygotes all carried a second missense variant on the second allele (Lefaucheur et al. 2008; Cozar et al. 2011). The p.Asp444Asn variant was absent from 80 controls but is reported at a frequency of 0.00134 in the Latino population of the Genome Aggregation Database. Functional studies were performed using cultured fibroblasts from a patient and showed that the p.Asp444Asn variant was not stimulated by physiological levels of S-Adenosylmethionine (AdoMet; a protein which stimulates CBS activity) compared to control fibroblasts, and required increased levels for stimulation (Kluijtmans et al. 1996; Evande et al. 2002). In addition, a study by Hnizda et al. (2012) evaluated protein folding and suggested that C-terminal regulatory domain variants, including the p.Asp444Asn variant, increased protein structural stability and decreased flexibility. Based on the collective evidence, the p.Asp444Asn variant is classified as pathogenic for homocystinuria. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population.
Integrated Genetics/Laboratory Corporation of America RCV000781196 SCV000919081 pathogenic Homocystinuria 2017-10-30 criteria provided, single submitter clinical testing Variant summary: The CBS c.1330G>A (p.Asp444Asn) variant involves the alteration of a conserved nucleotide that lies within the CBS domain (InterPro). 3/4 in silico tools predict a benign outcome for this variant (SNPsandGO not captured due to low reliability index). This variant was found in 65/192534 control chromosomes at a frequency of 0.0003376, which does not exceed the estimated maximal expected allele frequency of a pathogenic CBS variant (0.0030414). The variant has been reported in numerous patients with CBS-related homocystinuria, including homozygous patients. Functional studies suggest that CBS expression and activity levels are similar to those found in heterozygous individuals, but binding with the necessary cofactor S-adenosylmethionine and the subsequent induction of CBS protein activity is impaired (Mendes_2013). In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as pathogenic. Taken together, this variant is classified as pathogenic.
Invitae RCV000174656 SCV000543508 pathogenic Homocystinuria due to CBS deficiency 2017-12-27 criteria provided, single submitter clinical testing This sequence change replaces aspartic acid with asparagine at codon 444 of the CBS protein (p.Asp444Asn). The aspartic acid residue is highly conserved and there is a small physicochemical difference between aspartic acid and asparagine. This variant is present in population databases (rs28934891, ExAC 0.07%). This variant has been reported in the homozygous state in more than four individuals affected with homocystinuria (PMID: 8755636, 21520339, 16479318, 14972327). In addition, it was observed in the compound heterozygous state in several other affected individuals (PMID: 12007221, 18805305, 21520339). ClinVar contains an entry for this variant (Variation ID: 126). Multiple experimental studies have shown that this missense change has a deleterious effect on various aspects of CBS activity, ultimately leading to a loss of function (PMID: 8755636, 14722619, 20490928, 20506325, 22069143, 25044645). For these reasons, this variant has been classified as Pathogenic.
OMIM RCV000000148 SCV000020291 pathogenic Homocystinuria, pyridoxine-responsive 2004-01-01 no assertion criteria provided literature only
OMIM RCV000000149 SCV000020292 pathogenic HYPERHOMOCYSTEINEMIA, THROMBOTIC, CBS-RELATED 2004-01-01 no assertion criteria provided literature only
SIB Swiss Institute of Bioinformatics RCV000174656 SCV000803554 likely pathogenic Homocystinuria due to CBS deficiency 2018-05-31 criteria provided, single submitter curation This variant is interpreted as a Likely Pathogenic, for Cystathionine beta-synthase deficiency, in Autosomal Recessive manner. The following ACMG Tag(s) were applied: PS3 => Well-established functional studies show a deleterious effect (PMID:12269827,23974653,20506325,8755636). PM2 => Absent from controls (or at extremely low frequency if recessive; or below the expected carrier frequency if recessive disease or below disease prevalence if dominant disease) in Exome Sequencing Project, 1000 Genomes Project, or Exome Aggregation Consortium. PM3 => For recessive disorders, detected in trans with a pathogenic variant (PMID:23974653). PP1 => Cosegregation with disease in multiple affected family members in a gene definitively known to cause the disease (PMID:8755636,).

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