Submissions for variant NM_000071.3(CBS):c.233C>G (p.Pro78Arg)

dbSNP: rs786204608

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Counsyl	RCV000169367	SCV000220742	likely pathogenic	Classic homocystinuria	2014-09-26	criteria provided, single submitter	literature only
Ambry Genetics	RCV002444679	SCV002732600	uncertain significance	Familial thoracic aortic aneurysm and aortic dissection	2018-06-21	criteria provided, single submitter	clinical testing	The p.P78R variant (also known as c.233C>G), located in coding exon 2 of the CBS gene, results from a C to G substitution at nucleotide position 233. The proline at codon 78 is replaced by arginine, an amino acid with dissimilar properties. This alteration was reported as occurring in cis with p.K102N as a complex allele [P78R:K102N] in three siblings with homocystinuria who had p.E239K in trans. The same study also reported that the complex allele led to abolished CBS activity, while the individual variants resulted in reduced activity (de Franchis R et al. Hum. Mol. Genet., 1994 Jul;3:1103-8). The double variant was revealed to lose AdoMet-dependent regulation (Sen S et al. Biochemistry, 2007 Apr;46:4110-6). In addition, follow-up research suggested that the reduced activity of the individual variants might be rescued to some extent by improving protein folding (Kozich V et al. Hum. Mutat., 2010 Jul;31:809-19; Kopecká J et al. J. Inherit. Metab. Dis., 2011 Feb;34:39-48). However, in yeast assays, this alteration was described to behave similarly to wildtype (Mayfield JA et al. Genetics, 2012 Apr;190:1309-23), and no obvious biophysical difference has been observed (Majtan T et al. J. Biol. Chem., 2010 May;285:15866-73; Hnízda A et al. Biochemistry, 2012 Jun;51:4755-63; Pey AL et al. Biochem. J., 2013 Jan;449:109-21). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this variant remains unclear.
Invitae	RCV002515196	SCV002978951	uncertain significance	HYPERHOMOCYSTEINEMIA, THROMBOTIC, CBS-RELATED	2022-06-14	criteria provided, single submitter	clinical testing	This sequence change replaces proline, which is neutral and non-polar, with arginine, which is basic and polar, at codon 78 of the CBS protein (p.Pro78Arg). This variant is present in population databases (rs786204608, gnomAD 0.0009%). This missense change has been observed in individual(s) with CBS deficiency (PMID: 7967489). ClinVar contains an entry for this variant (Variation ID: 188988). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Tolerated"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C0"). Experimental studies are conflicting or provide insufficient evidence to determine the effect of this variant on CBS function (PMID: 7981678, 20308073, 22612060, 25331909). 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	RCV003226232	SCV003922487	uncertain significance	not specified	2023-03-15	criteria provided, single submitter	clinical testing	Variant summary: CBS c.233C>G (p.Pro78Arg) results in a non-conservative amino acid change in 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 4e-06 in 251194 control chromosomes. c.233C>G has been reported in the literature as a complex allele in cis alongside c.306G>C (p.Lys102Asn) in a biparentally confirmed compound heterozygous genotype with c.715G>A (p.E239K) (not reported in ClinVar) in trans in two affected siblings with features of Homocystinuria and their unaffected brother (deFranchis_1994). These report(s) do not provide unequivocal conclusions about association of the variant with Homocystinuria. Multiple publications report conflicting variant specific experimental evidence evaluating an impact on protein function in vitro (example, deFranchis_1994, Sen_2007, Mayfield_2012, Hnizda_2012, Melenovska_2015, Majtan_2010). The most pronounced variant effect results in CBS activities ranging from 10%-<30%, 30-50% or >50-90% of normal depending upon the expression systems and kinetic parameters evaluated (Ecoli, Yeast, CHO-K1 cells). The complex allele of Pro78Arg+Lys102Asn expressed in cis had 0% activity (deFranchis_1994). Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.