ClinVar Miner

Submissions for variant NM_003748.4(ALDH4A1):c.866+1G>A (rs78532707)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000505674 SCV000826155 likely pathogenic Deficiency of pyrroline-5-carboxylate reductase 2018-09-19 criteria provided, single submitter clinical testing This sequence change affects a donor splice site in intron 8 of the ALDH4A1 gene. It is expected to disrupt RNA splicing and likely results in an absent or disrupted protein product. This variant is present in population databases (rs78532707, ExAC 0.009%). This variant has not been reported in the literature in individuals with ALDH4A1-related disease. ClinVar contains an entry for this variant (Variation ID: 438800). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site, but this prediction has not been confirmed by published transcriptional studies. Donor and acceptor splice site variants typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in ALDH4A1 are known to be pathogenic (PMID: 9700195, 4369405, 956388). 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.
Illumina Clinical Services Laboratory,Illumina RCV000505674 SCV000914371 uncertain significance Deficiency of pyrroline-5-carboxylate reductase 2018-11-19 criteria provided, single submitter clinical testing The ALDH4A1 c.866+1G>A variant occurs in a canonical splice site (donor) and is therefore predicted to disrupt or distort the normal gene product. It was observed by ICSL as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018) and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score for this variant, it could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene and cDNA change. No publications were found based on this search. Due to the potential impact of splice donor variants and the lack of clarifying evidence, this variant is classified as a variant of unknown significance but suspicious for pathogenicity for hyperprolinemia.
Donald Williams Parsons Laboratory,Baylor College of Medicine RCV000505674 SCV000599974 pathogenic Deficiency of pyrroline-5-carboxylate reductase 2014-11-17 no assertion criteria provided research This splice site variant is categorized as deleterious according to ACMG guidelines (PMID:18414213). It would be pathogenic in a recessive state; heterozygotes would be carriers for the condition. It was found once in our study heterozygous, maternally inherited in a 12-year-old female with pilocytic astrocytoma and intellectual disability.

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