ClinVar Miner

Submissions for variant NM_000071.2(CBS):c.572C>T (p.Thr191Met) (rs121964973)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Counsyl RCV000576767 SCV000677987 pathogenic Homocystinuria due to CBS deficiency 2015-10-27 criteria provided, single submitter clinical testing
GeneDx RCV000195441 SCV000249685 pathogenic not provided 2016-09-12 criteria provided, single submitter clinical testing p.Thr191Met (ACG>ATG): c.572 C>T in exon 7 of the CBS gene (NM_000071.2). The T191M missense mutation in the CBS gene has been reported previously in association with homocystinuria due to cystathionine beta-synthase (CBS) deficiency (Kraus et al., 1999). In vitro functional studies found that CBS protein harboring the T191M mutation had extensive unfolding with decreased stability (Hnizda et al., 2012). T191M results in a non-conservative amino acid substitution at a position that is conserved across species. Mutations in nearby residues (D198V, P200L) have been reported in association with homocystinuria, further supporting the functional importance of this region of the protein. Furthermore, the T191M mutation was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. In summary, T191M in the CBS gene is interpreted as a disease-causing mutation. This variant was found in TAADV2-1,CBS
Integrated Genetics/Laboratory Corporation of America RCV000589097 SCV000695307 pathogenic Homocystinuria 2017-06-05 criteria provided, single submitter clinical testing Variant summary: The CBS c.572C>T (p.Thr191Met) variant involves the alteration of a conserved nucleotide, is located in dimer interface of the active core of the protein (Hnizda_2012) and is predicted to be damaging by 5/5 in silico tools. Multiple functional studies show that this variant causes severe impairment in protein structure and/or function (Kraus_1999, Kraus_2012, Mayfield_2012). This variant is absent in 117282 control chromosomes from ExAC. This variant is a known common pathogenic variant that causes homocystinuria. It is highly prevalent in homocystinuric patients from Spain, Portugal and South America. Genotype-phenotype correlation study show this variant leads to non-responsiveness to vitamin B6. One clinical laboratory and one reputable database (via ClinVar) have have classified this variant as pathogenic. Taken together, this variant is classified as pathogenic.
Invitae RCV000576767 SCV000769933 pathogenic Homocystinuria due to CBS deficiency 2018-12-21 criteria provided, single submitter clinical testing This sequence change replaces threonine with methionine at codon 191 of the CBS protein (p.Thr191Met). The threonine residue is highly conserved and there is a moderate physicochemical difference between threonine and methionine. This variant is not present in population databases (ExAC no frequency). This variant has been reported as homozygous or in combination with another CBS variant in several individuals affected with homocystinuria (PMID: 12815602, 15993874, 16470595, 16479318, 25218699). ClinVar contains an entry for this variant (Variation ID: 132). Experimental studies have shown that this missense change reduces CBS protein stability and enzyme activity (PMID: 22267502, 10338090, 22069143, 16429402). For these reasons, this variant has been classified as Pathogenic.
OMIM RCV000000155 SCV000020298 pathogenic Homocystinuria, pyridoxine-nonresponsive 2006-01-01 no assertion criteria provided literature only

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