ClinVar Miner

Submissions for variant NM_000071.3(CBS):c.1643G>A (p.Arg548Gln)

gnomAD frequency: 0.00105  dbSNP: rs150828989
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Total submissions: 10
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV001312008 SCV000249716 likely benign not provided 2021-03-30 criteria provided, single submitter clinical testing This variant is associated with the following publications: (PMID: 16429402)
Invitae RCV002229440 SCV000283384 benign HYPERHOMOCYSTEINEMIA, THROMBOTIC, CBS-RELATED 2024-02-01 criteria provided, single submitter clinical testing
Ambry Genetics RCV002310760 SCV000317729 likely benign Familial thoracic aortic aneurysm and aortic dissection 2018-03-20 criteria provided, single submitter clinical testing This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories RCV001312008 SCV001157106 likely benign not provided 2023-11-30 criteria provided, single submitter clinical testing
Illumina Laboratory Services, Illumina RCV000227198 SCV001303143 likely benign Classic homocystinuria 2017-04-27 criteria provided, single submitter clinical testing This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign.
CeGaT Center for Human Genetics Tuebingen RCV001312008 SCV001502420 likely benign not provided 2024-02-01 criteria provided, single submitter clinical testing CBS: PM5:Supporting, PS3:Supporting, BS2
Fulgent Genetics, Fulgent Genetics RCV000227198 SCV002807413 likely benign Classic homocystinuria 2022-01-21 criteria provided, single submitter clinical testing
PreventionGenetics, part of Exact Sciences RCV003955179 SCV004769507 likely benign CBS-related disorder 2022-02-18 criteria provided, single submitter clinical testing This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications).
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV003987439 SCV004803539 likely benign not specified 2024-01-22 criteria provided, single submitter clinical testing Variant summary: CBS c.1643G>A (p.Arg548Gln) results in a conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.0016 in 249094 control chromosomes, including one homozygote, and predominantly at a frequency of 0.0025 within the Non-Finnish European subpopulation in the gnomAD database. This frequency is approximately equal to the maximum frequency estimated for a pathogenic variant in CBS causing Homocystinuria (0.0025 vs 0.003), suggesting the variant could be a benign polymorphism found primarily in individuals of Non-Finnish European ancestry. c.1643G>A has been reported in the literature in the heterozygous state in an individual affected with Homocystinuria in whom no other CBS variants were identified (Urreizti_2006). This report does not provide unequivocal conclusions about association of the variant with Homocystinuria. A functional study found the variant retained approximately 60% of WT activity, responded to cofactor and allosteric activator similar to the WT enzyme, and was able to form tetramers in vitro (Urreizti_2006). The following publication has been ascertained in the context of this evaluation (PMID: 16429402).ClinVar contains an entry for this variant (Variation ID: 212869). Based on the evidence outlined above, the variant was classified as likely benign.
Natera, Inc. RCV000227198 SCV002083753 likely benign Classic homocystinuria 2021-02-26 no assertion criteria provided clinical testing

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