ClinVar Miner

Submissions for variant NM_002860.4(ALDH18A1):c.991A>C (p.Thr331Pro)

gnomAD frequency: 0.00001  dbSNP: rs765380273
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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000429762 SCV000535969 uncertain significance not provided 2021-01-05 criteria provided, single submitter clinical testing Has not been previously published as pathogenic or benign to our knowledge; Not observed at a significant frequency in large population cohorts (Lek et al., 2016); In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function
HudsonAlpha Institute for Biotechnology, HudsonAlpha Institute for Biotechnology RCV000850403 SCV000992600 uncertain significance Spondyloepiphyseal dysplasia, Stanescu type 2018-04-17 criteria provided, single submitter research
Ambry Genetics RCV002525501 SCV003556351 uncertain significance Inborn genetic diseases 2021-06-25 criteria provided, single submitter clinical testing The c.991A>C (p.T331P) alteration is located in exon 9 (coding exon 8) of the ALDH18A1 gene. This alteration results from a A to C substitution at nucleotide position 991, causing the threonine (T) at amino acid position 331 to be replaced by a proline (P). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear.
Baylor Genetics RCV003147460 SCV003835808 likely pathogenic Autosomal recessive complex spastic paraplegia type 9B 2022-10-23 criteria provided, single submitter clinical testing
Labcorp Genetics (formerly Invitae), Labcorp RCV003766464 SCV004571923 likely pathogenic Cutis laxa, autosomal dominant 3; Autosomal dominant spastic paraplegia type 9; de Barsy syndrome 2023-08-27 criteria provided, single submitter clinical testing ClinVar contains an entry for this variant (Variation ID: 392663). This missense change has been observed in individuals with clinical features of autosomal recessive hereditary spastic paraplegia (PMID: 36067040). It has also been observed to segregate with disease in related individuals. This variant is present in population databases (rs765380273, gnomAD 0.003%). This sequence change replaces threonine, which is neutral and polar, with proline, which is neutral and non-polar, at codon 331 of the ALDH18A1 protein (p.Thr331Pro). 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) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on ALDH18A1 protein function. 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. Experimental studies are conflicting or provide insufficient evidence to determine the effect of this variant on ALDH18A1 function (PMID: 36067040).
OMIM RCV003152603 SCV003841149 pathogenic ALDH18A1-related de Barsy syndrome 2023-03-14 no assertion criteria provided literature only

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