Total submissions: 4
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Illumina Laboratory Services, |
RCV000778630 | SCV000914954 | uncertain significance | Hypermethioninemia with deficiency of S-adenosylhomocysteine hydrolase | 2018-12-07 | criteria provided, single submitter | clinical testing | The AHCY gene c.257A>G (p.Asp86Gly) variant is a missense variant that has been reported in two studies and found in one sibling-pair with AHCY deficiency in a compound heterozygous state with another missense variant (Vugrek et al. 2009; Grubbs et al. 2010). The p.Asp86Gly variant was inherited from the mother and the other missense variant (p.Arg49Cys) was inherited from the father. Control data are unavailable for this variant, which is reported at a frequency of 0.00008 in the European (non-Finnish) population of the Exome Aggregation Consortium. Functional evidence from expression of the p.Asp86Gly protein in E.coli showed reduced AHCY activity as measured by enzyme assays, and PAGE studies showed enzymatically inactive aggregates (Vugrek et al. 2009). Based on the evidence, the p.Asp86Gly variant is considered to be a variant of unknown significance but suspicious for pathogenicity for hypermethioninemia. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population. |
| Ambry Genetics | RCV001266439 | SCV001444614 | likely pathogenic | Inborn genetic diseases | 2018-11-21 | criteria provided, single submitter | clinical testing | |
| Labcorp Genetics |
RCV000778630 | SCV003260688 | pathogenic | Hypermethioninemia with deficiency of S-adenosylhomocysteine hydrolase | 2023-08-17 | criteria provided, single submitter | clinical testing | This sequence change replaces aspartic acid, which is acidic and polar, with glycine, which is neutral and non-polar, at codon 86 of the AHCY protein (p.Asp86Gly). This variant is present in population databases (rs773162208, gnomAD 0.006%). This missense change has been observed in individual(s) with S-adenosylhomocysteine hydrolase (AHCY) deficiency (PMID: 20852937). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 631872). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt AHCY protein function. Experimental studies have shown that this missense change affects AHCY function (PMID: 19177456). For these reasons, this variant has been classified as Pathogenic. |
| OMIM | RCV000778630 | SCV004244390 | pathogenic | Hypermethioninemia with deficiency of S-adenosylhomocysteine hydrolase | 2024-02-06 | no assertion criteria provided | literature only |