ClinVar Miner

Submissions for variant NM_014305.4(TGDS):c.298G>T (p.Ala100Ser)

gnomAD frequency: 0.00041  dbSNP: rs140430952
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Total submissions: 11
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000624586 SCV000741616 pathogenic Inborn genetic diseases 2016-06-20 criteria provided, single submitter clinical testing
Fulgent Genetics, Fulgent Genetics RCV000149817 SCV000893333 pathogenic Catel-Manzke syndrome 2018-10-31 criteria provided, single submitter clinical testing
CeGaT Center for Human Genetics Tuebingen RCV001092080 SCV001248438 pathogenic not provided 2018-02-01 criteria provided, single submitter clinical testing
HudsonAlpha Institute for Biotechnology, HudsonAlpha Institute for Biotechnology RCV000149817 SCV001439371 pathogenic Catel-Manzke syndrome 2020-08-26 criteria provided, single submitter research ACMG codes:PS4, PM2, PM3, PP3, PP5
GeneDx RCV001092080 SCV001795815 pathogenic not provided 2023-08-23 criteria provided, single submitter clinical testing In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 28422407, 26366375, 25480037, 24326962, 21834032, 18501694, 14564220, 34426522, 31769200, 31833187, 34012376, 34930662, 29431110, 27535533)
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000149817 SCV002572361 pathogenic Catel-Manzke syndrome 2022-08-26 criteria provided, single submitter clinical testing Variant summary: TGDS c.298G>T (p.Ala100Ser) results in a conservative amino acid change located in the NAD(P)-binding domain (IPR016040) of 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 0.00033 in 206418 control chromosomes. This frequency does not allow conclusions about variant significance. c.298G>T has been reported in the literature as a biallelic genotype in multiple individuals affected with Catel-Manzke Syndrome (example, Ehmke_2014, Miller_2020). These data indicate that the variant is very likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Six clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Invitae RCV001092080 SCV003258522 pathogenic not provided 2022-09-21 criteria provided, single submitter clinical testing This sequence change replaces alanine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 100 of the TGDS protein (p.Ala100Ser). This variant is present in population databases (rs140430952, gnomAD 0.06%). This missense change has been observed in individuals with atypical or typical Catel-Manzke syndrome (PMID: 25480037, 26366375, 28422407, 31769200). ClinVar contains an entry for this variant (Variation ID: 162455). 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 TGDS protein function. For these reasons, this variant has been classified as Pathogenic.
Revvity Omics, Revvity Omics RCV000149817 SCV003811576 likely pathogenic Catel-Manzke syndrome 2021-12-22 criteria provided, single submitter clinical testing
Preventiongenetics, part of Exact Sciences RCV003415988 SCV004118257 pathogenic TGDS-related condition 2023-08-03 criteria provided, single submitter clinical testing The TGDS c.298G>T variant is predicted to result in the amino acid substitution p.Ala100Ser. This variant has been reported as a most common pathogenic variant for Catel-Manzke Syndrome (Ehmke. 2014. PubMed ID: 25480037; Pferdehirt et al. 2015. PubMed ID: 26366375; Schoner et al. 2017. PubMed ID: 28422407). This variant is reported in 0.063% of alleles in individuals of European (Non-Finnish) descent in gnomAD (http://gnomad.broadinstitute.org/variant/13-95243122-C-A). This variant is interpreted as pathogenic.
OMIM RCV000149817 SCV000196644 pathogenic Catel-Manzke syndrome 2014-12-04 no assertion criteria provided literature only
Equipe Genetique des Anomalies du Developpement, Université de Bourgogne RCV000149817 SCV001439349 pathogenic Catel-Manzke syndrome 2020-09-25 no assertion criteria provided clinical testing

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