Submissions for variant NM_001082971.2(DDC):c.1234C>T (p.Arg412Trp)

gnomAD frequency: 0.00001  dbSNP: rs542063660

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV001380420	SCV001578489	pathogenic	Deficiency of aromatic-L-amino-acid decarboxylase	2023-08-25	criteria provided, single submitter	clinical testing	For these reasons, this variant has been classified as Pathogenic. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. Experimental studies have shown that this missense change affects DDC function (PMID: 24865461). 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) performed at Invitae indicates that this missense variant is expected to disrupt DDC protein function. ClinVar contains an entry for this variant (Variation ID: 1068764). This missense change has been observed in individual(s) with aromatic L-amino acid decarboxylase deficiency (PMID: 18567514, 28856607, 31975548). This variant is present in population databases (rs542063660, gnomAD 0.01%). This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 412 of the DDC protein (p.Arg412Trp).
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001380420	SCV005039573	pathogenic	Deficiency of aromatic-L-amino-acid decarboxylase	2024-03-11	criteria provided, single submitter	clinical testing	Variant summary: DDC c.1234C>T (p.Arg412Trp) results in a non-conservative amino acid change in the encoded protein sequence. Four 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 251426 control chromosomes. c.1234C>T has been reported in the literature in multiple individuals affected with Deficiency Of Aromatic-L-Amino-Acid Decarboxylase. 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 activity. ClinVar contains an entry for this variant (Variation ID: 1068764). Based on the evidence outlined above, the variant was classified as pathogenic.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV004545219	SCV005040793	pathogenic	RASopathy	2024-03-11	criteria provided, single submitter	clinical testing	Variant summary: LZTR1 c.1234C>T (p.Arg412Cys) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 4.2e-06 in 238628 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.1234C>T was reported as a de-novo mutation in one Japanese child with symptoms of Noonan Syndrome in a poster presentation at a scientific meeting (Dateki et al, ESPE, 2018), indicating that the variant may be associated with Noonan Syndrome, however this occurrence has not (to the best of our knowledge) been subsequently published in a peer-reviewed journal. Therefore, this information does not provide unequivocal conclusions about association of the variant with Noonan Syndrome. To our knowledge, no reports of c.1234C>T in individuals affected with Noonan Syndrome and no experimental evidence demonstrating an impact on protein function have been published in the literature. Three other clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories cited the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.
Clinical Laboratory Sciences Program (CLSP), King Saud bin Abdulaziz University for Health Sciences (KSAU-HS)	RCV001380420	SCV003927888	likely pathogenic	Deficiency of aromatic-L-amino-acid decarboxylase	2023-04-01	no assertion criteria provided	clinical testing