ClinVar Miner

Submissions for variant NM_000071.2(CBS):c.785C>T (p.Thr262Met) (rs149119723)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Counsyl RCV000180461 SCV000486524 likely pathogenic Homocystinuria due to CBS deficiency 2016-06-21 criteria provided, single submitter clinical testing
EGL Genetic Diagnostics,Eurofins Clinical Diagnostics RCV000200469 SCV000232906 pathogenic not provided 2014-11-21 criteria provided, single submitter clinical testing
GeneDx RCV000200469 SCV000249693 pathogenic not provided 2018-10-09 criteria provided, single submitter clinical testing The T262M has been published as a homozygous variant in several unrelated patients with homocystinuria referred for genetic testing at GeneDx and in published literature (Kim et al., 1997; Moat et al., 2004). This variant has also been reported in compound heterozygous patients with homocystinuria (Gallagher et al., 1998; Yap et al., 2017). Expression studies in yeast indicate that the T262M missense change severely affects cystathionine beta-synthase enzyme activity (Kim et al., 1997; Singh et al., 2007; Mayfield et al., 2012). The T262M variant results in a non-conservative amino acid substitution at a position where only amino acids with similar properties to threonine (T) are tolerated across species. A missense variant in the same residue (T262R) has been reported in HGMD in association with homocysteinuria (Stenson et al., 2014). Furthermore, the T262M variant is not observed at a significant frequency in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server).
Invitae RCV000180461 SCV000649850 pathogenic Homocystinuria due to CBS deficiency 2017-12-27 criteria provided, single submitter clinical testing This sequence change replaces threonine with methionine at codon 262 of the CBS protein (p.Thr262Met). The threonine residue is moderately conserved and there is a moderate physicochemical difference between threonine and methionine. This variant is present in population databases (rs149119723, ExAC 0.002%). This variant has been reported as homozygous or in combination with another CBS variant in several individuals affected with homocystinuria (PMID: 9889017, 10338090, 14722927). ClinVar contains an entry for this variant (Variation ID: 198988). This variant has been observed in an individual with very elevated homocysteine, and signs and symptoms highly specific for homocystinuria (PMID: 9361025). Experimental studies have shown that this missense change disrupts CBS protein function in vitro (PMID: 9361025, 22267502). For these reasons, this variant has been classified as Pathogenic.

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