ClinVar Miner

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

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
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).
Counsyl RCV000180461 SCV000486524 likely pathogenic Classic homocystinuria 2016-06-21 criteria provided, single submitter clinical testing
Invitae RCV000180461 SCV000649850 pathogenic Classic homocystinuria 2020-10-25 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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV001251422 SCV001427013 pathogenic Homocystinuria 2020-07-31 criteria provided, single submitter clinical testing Variant summary: CBS c.785C>T (p.Thr262Met) results in a non-conservative amino acid change located in the Pyridoxal-phosphate dependent enzyme domain (IPR001926) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 2.8e-05 in 249602 control chromosomes (gnomAD and publication data). c.785C>T has been reported in the literature in multiple individuals affected with Homocystinuria, including one homozygote (Kim_1997, Kraus_1999, Al-Sadeq DW_2020). These data indicate that the variant is very likely to be associated with disease. In vitro study reports this variant has an impact on protein function and results in <10% of normal CBS activity in yeast. Three ClinVar submitters (evaluation after 2014) cite the variant as pathogenic (2x) and likely pathogenic (1x). Based on the evidence outlined above, the variant was classified as pathogenic.

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