ClinVar Miner

Submissions for variant NM_001082971.2(DDC):c.823G>A (p.Ala275Thr)

gnomAD frequency: 0.00003  dbSNP: rs137853212
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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Labcorp Genetics (formerly Invitae), Labcorp RCV000019392 SCV002132315 uncertain significance Deficiency of aromatic-L-amino-acid decarboxylase 2022-04-11 criteria provided, single submitter clinical testing This sequence change replaces alanine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 275 of the DDC protein (p.Ala275Thr). This variant is present in population databases (rs137853212, gnomAD 0.007%). This missense change has been observed in individual(s) with aromatic L-amino acid decarboxylase deficiency (PMID: 9789536, 30952622). ClinVar contains an entry for this variant (Variation ID: 17814). 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 disruptive. Experimental studies have shown that this missense change affects DDC function (PMID: 21541720). 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.
GeneDx RCV004700253 SCV005202117 likely pathogenic not provided 2023-11-03 criteria provided, single submitter clinical testing Published functional studies demonstrate a reduction in catalytic efficiency and PLP binding affinity (PMID: 21541720); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 21541720, 36427457, 9789536)
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000019392 SCV005886712 pathogenic Deficiency of aromatic-L-amino-acid decarboxylase 2025-02-03 criteria provided, single submitter clinical testing Variant summary: DDC c.823G>A (p.Ala275Thr) results in a non-conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 1.2e-05 in 250978 control chromosomes (gnomAD). c.823G>A has been reported in the literature in multiple individuals affected with Deficiency Of Aromatic-L-Amino-Acid Decarboxylase (e.g. Himmelreich_2023). These data indicate that the variant is very likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function. The most pronounced variant effect results in <10% of normal enzymatic activity (Montioli_2011). The following publications have been ascertained in the context of this evaluation (PMID: 37348148, 21541720). ClinVar contains an entry for this variant (Variation ID: 17814). Based on the evidence outlined above, the variant was classified as pathogenic.
3billion RCV000019392 SCV005906066 likely pathogenic Deficiency of aromatic-L-amino-acid decarboxylase 2023-10-13 criteria provided, single submitter clinical testing The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.001%). Predicted Consequence/Location: Missense variant Functional studies provide strong evidence of the variant having a damaging effect on the gene or gene product (PMID: 21541720, 36427457). In silico tool predictions suggest damaging effect of the variant on gene or gene product [3Cnet: 0.90 (>=0.6, sensitivity 0.72 and precision 0.9)]. The variant has been reported to be in trans with a pathogenic variant as either compound heterozygous or homozygous in at least one similarly affected unrelated individual (PMID: 30952622). Therefore, this variant is classified as Likely pathogenic according to the recommendation of ACMG/AMP guideline.
OMIM RCV000019392 SCV000039682 pathogenic Deficiency of aromatic-L-amino-acid decarboxylase 2022-08-11 no assertion criteria provided literature only

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