Total submissions: 4
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Labcorp Genetics |
RCV000167587 | SCV002977378 | likely pathogenic | Homocystinuria due to methylene tetrahydrofolate reductase deficiency | 2023-01-27 | criteria provided, single submitter | clinical testing | In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated. ClinVar contains an entry for this variant (Variation ID: 187867). This missense change has been observed in individual(s) with severe MTHFR deficiency (PMID: 25736335, 28241805). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. This variant is present in population databases (rs776483190, gnomAD 0.003%). This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 46 of the MTHFR protein (p.Arg46Gln). |
| Women's Health and Genetics/Laboratory Corporation of America, |
RCV000167587 | SCV004099825 | likely pathogenic | Homocystinuria due to methylene tetrahydrofolate reductase deficiency | 2023-09-01 | criteria provided, single submitter | clinical testing | Variant summary: MTHFR c.137G>A (p.Arg46Gln) 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 2e-05 in 251332 control chromosomes (gnomAD). c.137G>A has been reported in the literature in individuals affected with Homocystinuria Due To Methylene Tetrahydrofolate Reductase Deficiency (Burda_2015, Iida_2017, Crass_2020). These data indicate that the variant may be associated with disease. At least two publications report experimental evidence evaluating an impact on protein function. The most pronounced variant effect results in <10% of normal activity (Burda_2015, Weile_2021). The following publications have been ascertained in the context of this evaluation (PMID: 25736335, 33125268, 28241805, 34845156, 35008593, 34214447). One submitter has cited clinical-significance assessments for this variant to ClinVar after 2014 and has classified the variant as likely pathogenic. Based on the evidence outlined above, the variant was classified as likely pathogenic. |
| Baylor Genetics | RCV003468812 | SCV004196426 | likely pathogenic | Neural tube defects, folate-sensitive | 2024-03-16 | criteria provided, single submitter | clinical testing | |
| University Children's Hospital, |
RCV000167587 | SCV000218468 | pathogenic | Homocystinuria due to methylene tetrahydrofolate reductase deficiency | no assertion criteria provided | clinical testing |