Submissions for variant NM_000071.3(CBS):c.152G>A (p.Arg51Lys)

gnomAD frequency: 0.00003  dbSNP: rs370983323

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000486724	SCV000569322	uncertain significance	not provided	2016-02-10	criteria provided, single submitter	clinical testing	A variant of uncertain significance has been identified in the CBS gene. The R51K variant has not been published as a pathogenic variant, nor has it been reported as a benign variant to our knowledge. The R51K variant was not observed with any significant frequency in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project. However, the R51K variant is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties. This substitution occurs at a position where amino acids with similar properties to Arginine are tolerated across species. Finally, in silico analysis is inconsistent in its predictions as to whether or not the variant is damaging to the protein structure/function.
Invitae	RCV002231109	SCV001490512	uncertain significance	HYPERHOMOCYSTEINEMIA, THROMBOTIC, CBS-RELATED	2024-01-22	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with lysine, which is basic and polar, at codon 51 of the CBS protein (p.Arg51Lys). This variant is present in population databases (rs370983323, gnomAD 0.01%). This variant has not been reported in the literature in individuals affected with CBS-related conditions. ClinVar contains an entry for this variant (Variation ID: 420469). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Not Available"; PolyPhen-2: "Benign"; Align-GVGD: "Not Available". The lysine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. 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.
Ambry Genetics	RCV002402397	SCV002708256	uncertain significance	Familial thoracic aortic aneurysm and aortic dissection	2018-11-17	criteria provided, single submitter	clinical testing	The p.R51K variant (also known as c.152G>A), located in coding exon 1 of the CBS gene, results from a G to A substitution at nucleotide position 152. The arginine at codon 51 is replaced by lysine, an amino acid with highly similar properties. This amino acid position is not well conserved in available vertebrate species, and lysine is the reference amino acid in other 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.
Natera, Inc.	RCV001301346	SCV002083831	uncertain significance	Classic homocystinuria	2020-10-14	no assertion criteria provided	clinical testing