Submissions for variant NM_000071.3(CBS):c.599C>T (p.Pro200Leu)

gnomAD frequency: 0.00002  dbSNP: rs758712880

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV002234274	SCV000935576	uncertain significance	HYPERHOMOCYSTEINEMIA, THROMBOTIC, CBS-RELATED	2022-07-19	criteria provided, single submitter	clinical testing	This sequence change replaces proline, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 200 of the CBS protein (p.Pro200Leu). This variant is present in population databases (rs758712880, gnomAD 0.003%). This missense change has been observed in individual(s) with homocystinuria (PMID: 21520339). ClinVar contains an entry for this variant (Variation ID: 642590). 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: "Deleterious"; 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: 21520339). 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.
Fulgent Genetics, Fulgent Genetics	RCV002495046	SCV002797596	uncertain significance	Classic homocystinuria	2021-07-28	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV003307441	SCV003999865	uncertain significance	Familial thoracic aortic aneurysm and aortic dissection	2023-04-22	criteria provided, single submitter	clinical testing	The p.P200L variant (also known as c.599C>T), located in coding exon 5 of the CBS gene, results from a C to T substitution at nucleotide position 599. The proline at codon 200 is replaced by leucine, an amino acid with similar properties. This alteration was reported in an individual with severe hyperhomocysteinemia; however, a second alteration in CBS was not identified (Cozar M et al. Hum Mutat, 2011 Jul;32:835-42). 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 alteration remains unclear.
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	RCV001530086	SCV001744698	uncertain significance	not provided		no assertion criteria provided	clinical testing
Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	RCV001530086	SCV001797596	uncertain significance	not provided		no assertion criteria provided	clinical testing