Submissions for variant NM_000071.3(CBS):c.1316G>A (p.Arg439Gln)

gnomAD frequency: 0.00003  dbSNP: rs756467921

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Counsyl	RCV000169494	SCV000220951	likely benign	Classic homocystinuria	2014-12-16	criteria provided, single submitter	literature only
Eurofins Ntd Llc (ga)	RCV000587586	SCV000331007	uncertain significance	not provided	2015-11-19	criteria provided, single submitter	clinical testing
Invitae	RCV003153461	SCV000543514	uncertain significance	HYPERHOMOCYSTEINEMIA, THROMBOTIC, CBS-RELATED	2022-09-26	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 439 of the CBS protein (p.Arg439Gln). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This missense change has been observed in individual(s) with homocystinuria, co-occuring in cis with another likely pathogenic variant (p.Glu144Lys). This variant also co-occurs in trans with other pathogenic variants in individuals with homocystinuria (PMID: 9156316, 10462600, 12124992). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 189088). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated. Experimental studies have shown that this missense change does not substantially affect CBS function (PMID: 9156316, 20490928, 20506325, 22069143, 22267502). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV003155100	SCV000695303	uncertain significance	not specified	2023-02-01	criteria provided, single submitter	clinical testing	Variant summary: CBS c.1316G>A (p.Arg439Gln) results in a conservative amino acid change located in the CBS domain (IPR000644) of the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 2.3e-05 in 171116 control chromosomes (gnomAD). The variant, c.1316G>A, has been reported in the literature in at least three individuals affected with Homocystinuria (Tsai_1997, Dawson_1997, Gaustadnes_2002), however two of these patients also carried a pathogenic variant (c.430G>A (p.Glu144Lys)) in cis. Multiple publications reported experimental evidence evaluating an impact on protein function, and although in an early study the variant was found to result in a moderately reduced enzyme activity (~30% of WT) in a bacterial expression system (Dawson_1997)), later studies found activities similar to wild type in bacterial-, yeast- and mammalian systems (Mayfield_2012, Kopecka_2011, Hnizda_2012, Melenovska_2015). Four other clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014, mostly without evidence for independent evaluation, and classified the variant as VUS (n=3) or benign (n=1). Based on the evidence outlined above, the variant was classified as uncertain significance.
Mendelics	RCV000169494	SCV001141297	benign	Classic homocystinuria	2019-05-28	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV003298197	SCV003999864	uncertain significance	Familial thoracic aortic aneurysm and aortic dissection	2023-06-04	criteria provided, single submitter	clinical testing	The p.R439Q variant (also known as c.1316G>A), located in coding exon 12 of the CBS gene, results from a G to A substitution at nucleotide position 1316. The arginine at codon 439 is replaced by glutamine, an amino acid with highly similar properties. This alteration was identified in cis with an additional alteration in CBS in individuals with homocystinuria (Dawson PA et al. Eur J Hum Genet, 1997;5:15-21; Tsai MY et al. Mol Diagn, 1997 Jun;2:129-133; Gaustadnes M et al. Hum Mutat, 2002 Aug;20:117-26). In vitro assays showed this alteration may not impact protein function (Dawson PA et al. Eur J Hum Genet, 1997;5:15-21; Mayfield JA et al. Genetics, 2012 Apr;190:1309-23). This amino acid position is not well conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
GeneDx	RCV000587586	SCV004022757	uncertain significance	not provided	2023-07-26	criteria provided, single submitter	clinical testing	Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant does not alter protein structure/function; Functional studies have not shown a significant impact on protein function (Kozich et al., 2010; Hnzda et al., 2012; Mayfield et al., 2012); This variant is associated with the following publications: (PMID: 22267502, 20490928, 22069143, 9156316, 19429038, 20506325)
Natera, Inc.	RCV000169494	SCV001461062	uncertain significance	Classic homocystinuria	2020-09-16	no assertion criteria provided	clinical testing