Submissions for variant NM_000071.2(CBS):c.430G>A (p.Glu144Lys) (rs121964966)

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Counsyl	RCV000169074	SCV000220242	likely pathogenic	Classic homocystinuria	2014-04-14	criteria provided, single submitter	literature only
EGL Genetic Diagnostics, Eurofins Clinical Diagnostics	RCV000723427	SCV000331006	pathogenic	not provided	2015-11-18	criteria provided, single submitter	clinical testing
Invitae	RCV000169074	SCV000649837	likely pathogenic	Classic homocystinuria	2020-06-29	criteria provided, single submitter	clinical testing	This sequence change replaces glutamic acid with lysine at codon 144 of the CBS protein (p.Glu144Lys). The glutamic acid residue is highly conserved and there is a small physicochemical difference between glutamic acid and lysine. This variant is present in population databases (rs121964966, ExAC 0.006%). This variant has been reported to co-occur in cis with the p.Arg439Gln variant in three individuals affected with homocystinuria (PMID: 9156316, 12124992). This variant has also been reported to co-occur in combination or in trans with other pathogenic variants in individuals with homocystinuria (PMID: 12124992, 7611293, 10215408). ClinVar contains an entry for this variant (Variation ID: 122). Experimental studies have shown that this variant severely impairs CBS enzyme activity in bacterial and yeast but not in higher eukaryotic cell systems (PMID: 22267502, 20506325, 25331909). In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.
CeGaT Praxis fuer Humangenetik Tuebingen	RCV000723427	SCV001246795	pathogenic	not provided	2018-08-01	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001251284	SCV001426817	pathogenic	Homocystinuria	2020-07-24	criteria provided, single submitter	clinical testing	Variant summary: CBS c.430G>A (p.Glu144Lys) results in a conservative amino acid change located in the Pyridoxal-phosphate dependent enzyme (IPR001926) of the encoded protein sequence. Four 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 250114 control chromosomes. c.430G>A has been reported in the literature in multiple individuals affected with Homocystinuria (e.g. Shih_1995, Gordon_1998, Janosik_2001, Guastadnes_2002,Kozich_2010). These data indicate that the variant is very likely to be associated with disease. In several of these cases, the variant has been reported to co-occur in cis with another variant that is cited as pathogenic (e.g. c.463G>A, p.A155T in Janosik_2001). Multiple publications report contrasting experimental evidence evaluating an impact on protein function. The variant was found to result in significantly reduced enzyme activtiy in yeast and bacterial cell lines (e.g. Gordon_1998, Kozich_2010, Mayfield_2012) but had no significant damaging effects in experiments in a mammalian cell line (Melenovska_2014). Three clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories cited the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen	RCV000723427	SCV001480070	pathogenic	not provided	2021-02-01	criteria provided, single submitter	clinical testing
GeneDx	RCV000723427	SCV001757529	pathogenic	not provided	2019-11-04	criteria provided, single submitter	clinical testing	Not observed at a significant frequency in large population cohorts (Lek et al., 2016); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; This variant is associated with the following publications: (PMID: 12124992, 25331909, 10215408, 20567906, 9156316, 11359213, 11748855, 15365998, 14722927, 7611293, 20506325, 22267502, 31301157)
OMIM	RCV000000144	SCV000020287	pathogenic	Homocystinuria, pyridoxine-responsive	1995-07-01	no assertion criteria provided	literature only