ClinVar Miner

Submissions for variant NM_000687.4(AHCY):c.428A>G (p.Tyr143Cys)

gnomAD frequency: 0.00009  dbSNP: rs121918608
Minimum review status: Collection method:
Minimum conflict level:
ClinVar version:
Total submissions: 9
Download table as spreadsheet
Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics RCV000224240 SCV000281169 likely pathogenic not provided 2014-05-19 criteria provided, single submitter clinical testing
Ambry Genetics RCV000624639 SCV000742929 pathogenic Inborn genetic diseases 2017-09-15 criteria provided, single submitter clinical testing
Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen RCV000224240 SCV001446643 likely pathogenic not provided 2020-10-23 criteria provided, single submitter clinical testing
GeneDx RCV000224240 SCV002107213 likely pathogenic not provided 2023-07-10 criteria provided, single submitter clinical testing Published functional studies of enzymatic assays showed that this variant reduced hydrolysis and synthesis to 25% and 34% of wildtype, suggesting a damaging effect (Beluzic et al., 2006); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 28647132, 34426522, 31589614, 28779239, 15024124, 18211827, 16736098, 33072517, 26095522, 16872278, 35463910)
Fulgent Genetics, Fulgent Genetics RCV000013819 SCV002787888 likely pathogenic Hypermethioninemia with deficiency of S-adenosylhomocysteine hydrolase 2024-04-15 criteria provided, single submitter clinical testing
Labcorp Genetics (formerly Invitae), Labcorp RCV000013819 SCV003459718 pathogenic Hypermethioninemia with deficiency of S-adenosylhomocysteine hydrolase 2024-11-19 criteria provided, single submitter clinical testing This sequence change replaces tyrosine, which is neutral and polar, with cysteine, which is neutral and slightly polar, at codon 143 of the AHCY protein (p.Tyr143Cys). This variant is present in population databases (rs121918608, gnomAD 0.02%). This missense change has been observed in individual(s) with clinical features of S-adenosylhomocysteine hydrolase deficiency (PMID: 15024124, 16736098, 28779239, 33072517). 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: 12953). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is expected to disrupt AHCY protein function with a positive predictive value of 95%. Experimental studies have shown that this missense change affects AHCY function (PMID: 16872278). For these reasons, this variant has been classified as Pathogenic.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000013819 SCV004020741 pathogenic Hypermethioninemia with deficiency of S-adenosylhomocysteine hydrolase 2023-06-30 criteria provided, single submitter clinical testing Variant summary: AHCY c.428A>G (p.Tyr143Cys) results in a non-conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 8e-05 in 250902 control chromosomes (gnomAD). c.428A>G has been reported in the literature as a biallelic genotype in multiple individuals affected with Hypermethioninemia with deficiency of S-adenosylhomocysteine hydrolase (e.g. Baric_2004, Baric_2005, Buist_2006), as well as in individuals affected with Neurodevelopmental Disorders (Soden_2014) and Rhabdomyolysis (Vivante_2017), which are associated phenotypes for Hypermethioninemia with deficiency of S-adenosylhomocysteine hydrolase. These data indicate that the variant is very likely to be associated with disease. Recombinant proteins purified from E.coli cultures showed the variant had reduced hydrolysis activity (25%) and reduced synthesis activity (34%) as compared to wild-type (Beluzic_2006). The following publications have been ascertained in the context of this evaluation (PMID: 16435181, 15024124, 16872278, 16736098, 25473036, 28779239). Six ClinVar submitters have assessed the variant since 2014: four classified the variant as likely pathogenic and two as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
OMIM RCV000013819 SCV000034066 pathogenic Hypermethioninemia with deficiency of S-adenosylhomocysteine hydrolase 2004-03-23 no assertion criteria provided literature only
Yale Center for Mendelian Genomics, Yale University RCV000662292 SCV000784620 likely pathogenic Rhabdomyolysis 2017-08-05 no assertion criteria provided literature only

The information on this website is not intended for direct diagnostic use or medical decision-making without review by a genetics professional. Individuals should not change their health behavior solely on the basis of information contained on this website. Neither the University of Utah nor the National Institutes of Health independently verfies the submitted information. If you have questions about the information contained on this website, please see a health care professional.