ClinVar Miner

Submissions for variant NM_003748.4(ALDH4A1):c.199G>A (p.Val67Met)

gnomAD frequency: 0.00070  dbSNP: rs141327098
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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Elsea Laboratory, Baylor College of Medicine RCV001250052 SCV001424204 uncertain significance Hyperprolinemia type 2 2020-04-01 criteria provided, single submitter clinical testing
Labcorp Genetics (formerly Invitae), Labcorp RCV001250052 SCV002166191 uncertain significance Hyperprolinemia type 2 2022-07-28 criteria provided, single submitter clinical testing This sequence change replaces valine, which is neutral and non-polar, with methionine, which is neutral and non-polar, at codon 67 of the ALDH4A1 protein (p.Val67Met). This variant is present in population databases (rs141327098, gnomAD 0.2%). This variant has not been reported in the literature in individuals affected with ALDH4A1-related conditions. ClinVar contains an entry for this variant (Variation ID: 973437). 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: "Probably Damaging"; Align-GVGD: "Class C0"). 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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV003987814 SCV004803700 uncertain significance not specified 2024-01-23 criteria provided, single submitter clinical testing Variant summary: ALDH4A1 c.199G>A (p.Val67Met) results in a conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.00018 in 1552904 control chromosomes, predominantly at a frequency of 0.0017 within the African or African-American subpopulation in the gnomAD database, including 1 homozygote. c.199G>A has been reported in the literature as a VUS in at least one individual affected with epilepsy without evidence for causality (e.g. Won_2020). These report(s) do not provide unequivocal conclusions about association of the variant with Deficiency of pyrroline-5-carboxylate reductase. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publication has been ascertained in the context of this evaluation (PMID: 32695065). ClinVar contains an entry for this variant (Variation ID: 973437). Based on the evidence outlined above, the variant was classified as uncertain significance.

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