ClinVar Genomic variation as it relates to human health
NM_014305.4(TGDS):c.298G>T (p.Ala100Ser)
The aggregate germline classification for this variant, typically for a monogenic or Mendelian disorder as in the ACMG/AMP guidelines, or for response to a drug. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the aggregate classification.
Stars represent the aggregate review status, or the level of review supporting the aggregate germline classification for this VCV record. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. The number of submissions which contribute to this review status is shown in parentheses.
No data submitted for somatic clinical impact
No data submitted for oncogenicity
Variant Details
- Identifiers
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NM_014305.4(TGDS):c.298G>T (p.Ala100Ser)
Variation ID: 162455 Accession: VCV000162455.42
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 13q32.1 13: 94590868 (GRCh38) [ NCBI UCSC ] 13: 95243122 (GRCh37) [ NCBI UCSC ]
- Timeline in ClinVar
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First in ClinVar Help The date this variant first appeared in ClinVar with each type of classification.
Last submission Help The date of the most recent submission for each type of classification for this variant.
Last evaluated Help The most recent date that a submitter evaluated this variant for each type of classification.
Germline Jan 17, 2015 Nov 10, 2024 Oct 31, 2024 - HGVS
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... more HGVS ... less HGVSNucleotide Protein Molecular
consequenceNM_014305.4:c.298G>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_055120.1:p.Ala100Ser missense NM_001304430.2:c.202G>T NP_001291359.1:p.Ala68Ser missense NR_130731.2:n.314G>T non-coding transcript variant NC_000013.11:g.94590868C>A NC_000013.10:g.95243122C>A NG_041837.1:g.10408G>T O95455:p.Ala100Ser - Protein change
- A100S, A68S
- Other names
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TGDS, ALA100SER (rs140430952)
- Canonical SPDI
- NC_000013.11:94590867:C:A
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Functional
consequence HelpThe effect of the variant on RNA or protein function, based on experimental evidence from submitters.
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Global minor allele
frequency (GMAF) HelpThe global minor allele frequency calculated by the 1000 Genomes Project. The minor allele at this location is indicated in parentheses and may be different from the allele represented by this VCV record.
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Allele frequency
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The frequency of the allele represented by this VCV record.
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The Genome Aggregation Database (gnomAD) 0.00041
Trans-Omics for Precision Medicine (TOPMed) 0.00047
NHLBI Exome Sequencing Project (ESP) Exome Variant Server 0.00077
- Links
Genes
| Gene | OMIM | ClinGen Gene Dosage Sensitivity Curation |
Variation Viewer
Help
Links to Variation Viewer, a genome browser to view variation data from NCBI databases. |
Related variants | ||
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| HI score
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The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
TS score
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The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
Within gene
Help
The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants. |
All
Help
The number of variants in ClinVar for this gene, including smaller variants within the gene and larger CNVs that overlap or fully contain the gene. |
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| TGDS | - | - |
GRCh38 GRCh37 |
83 | 177 | |
Conditions - Germline
| Condition
Help
The condition for this variant-condition (RCV) record in ClinVar. |
Classification
Help
The aggregate germline classification for this variant-condition (RCV) record in ClinVar. The number of submissions that contribute to this aggregate classification is shown in parentheses. (# of submissions) |
Review status
Help
The aggregate review status for this variant-condition (RCV) record in ClinVar. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. |
Last evaluated
Help
The most recent date that a submitter evaluated this variant for the condition. |
Variation/condition record
Help
The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page. |
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| Pathogenic/Likely pathogenic (6) |
criteria provided, multiple submitters, no conflicts
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Aug 26, 2022 | RCV000149817.13 | |
| Pathogenic (1) |
criteria provided, single submitter
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Jun 20, 2016 | RCV000624586.3 | |
| Pathogenic (3) |
criteria provided, multiple submitters, no conflicts
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Oct 31, 2024 | RCV001092080.28 | |
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TGDS-related disorder
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Pathogenic (1) |
no assertion criteria provided
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Dec 24, 2023 | RCV003415988.6 |
Submissions - Germline
| Classification
Help
The submitted germline classification for each SCV record. (Last evaluated) |
Review status
Help
Stars represent the review status, or the level of review supporting the submitted (SCV) record. This value is calculated by NCBI based on data from the submitter. Read our rules for calculating the review status. This column also includes a link to the submitter’s assertion criteria if provided, and the collection method. (Assertion criteria) |
Condition
Help
The condition for the classification, provided by the submitter for this submitted (SCV) record. This column also includes the affected status and allele origin of individuals observed with this variant. |
Submitter
Help
The submitting organization for this submitted (SCV) record. This column also includes the SCV accession and version number, the date this SCV first appeared in ClinVar, and the date that this SCV was last updated in ClinVar. |
More information
Help
This column includes more information supporting the classification, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter. |
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Pathogenic
(Oct 31, 2018)
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criteria provided, single submitter
Method: clinical testing
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Catel-Manzke syndrome
Affected status: unknown
Allele origin:
unknown
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Fulgent Genetics, Fulgent Genetics
Accession: SCV000893333.1
First in ClinVar: Mar 31, 2019 Last updated: Mar 31, 2019 |
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Pathogenic
(Feb 01, 2018)
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criteria provided, single submitter
Method: clinical testing
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not provided
Affected status: yes
Allele origin:
germline
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CeGaT Center for Human Genetics Tuebingen
Accession: SCV001248438.26
First in ClinVar: May 12, 2020 Last updated: Oct 20, 2024 |
Number of individuals with the variant: 1
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Pathogenic
(Aug 26, 2020)
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criteria provided, single submitter
Method: research
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Catel-Manzke syndrome
Affected status: yes
Allele origin:
inherited
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HudsonAlpha Institute for Biotechnology, HudsonAlpha Institute for Biotechnology
Study: CSER-SouthSeq
Accession: SCV001439371.1 First in ClinVar: Oct 31, 2020 Last updated: Oct 31, 2020 |
Comment:
ACMG codes:PS4, PM2, PM3, PP3, PP5
Clinical Features:
Birth length less than 3rd percentile (present) , Micrognathia (present) , Cleft palate (present) , Oligohydramnios (present)
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Pathogenic
(Aug 26, 2022)
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criteria provided, single submitter
Method: clinical testing
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Catel-Manzke syndrome
Affected status: unknown
Allele origin:
germline
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Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Accession: SCV002572361.1
First in ClinVar: Sep 17, 2022 Last updated: Sep 17, 2022 |
Comment:
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 … (more)
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. (less)
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Pathogenic
(Jun 20, 2016)
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criteria provided, single submitter
Method: clinical testing
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Inborn genetic diseases
Affected status: yes
Allele origin:
germline
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Ambry Genetics
Accession: SCV000741616.3
First in ClinVar: Apr 15, 2018 Last updated: Jan 07, 2023 |
Number of individuals with the variant: 1
Clinical Features:
Delayed speech and language development (present) , Micrognathia (present) , Narrow mouth (present) , Upslanted palpebral fissure (present) , High, narrow palate (present) , Abnormal … (more)
Delayed speech and language development (present) , Micrognathia (present) , Narrow mouth (present) , Upslanted palpebral fissure (present) , High, narrow palate (present) , Abnormal heart morphology (present) , Clinodactyly (present) , Abnormality of the cardiac septa (present) , Motor delay (present) , Abnormality of the hand (present) , Delayed speech and language development (present) , Micrognathia (present) , Narrow mouth (present) , Upslanted palpebral fissure (present) , High, narrow palate (present) , Abnormal heart morphology (present) , Clinodactyly (present) , Abnormality of the cardiac septa (present) , Motor delay (present) , Abnormality of the hand (present) (less)
Sex: female
Ethnicity/Population group: Caucasian
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Pathogenic
(Sep 21, 2022)
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criteria provided, single submitter
Method: clinical testing
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not provided
Affected status: unknown
Allele origin:
germline
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Labcorp Genetics (formerly Invitae), Labcorp
Accession: SCV003258522.1
First in ClinVar: Feb 07, 2023 Last updated: Feb 07, 2023 |
Comment:
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). … (more)
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. (less)
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Likely pathogenic
(Dec 22, 2021)
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criteria provided, single submitter
Method: clinical testing
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Catel-Manzke syndrome
Affected status: unknown
Allele origin:
germline
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Revvity Omics, Revvity
Accession: SCV003811576.2
First in ClinVar: Mar 04, 2023 Last updated: Feb 04, 2024 |
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Pathogenic
(Oct 31, 2024)
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criteria provided, single submitter
Method: clinical testing
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Not Provided
Affected status: yes
Allele origin:
germline
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GeneDx
Accession: SCV001795815.4
First in ClinVar: Aug 21, 2021 Last updated: Nov 10, 2024 |
Comment:
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, … (more)
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, 34426522, 31769200, 31833187, 34012376, 25480037, 34930662, 29431110, 37361548, 24326962, 21834032, 14564220, 37010288, 28229453, 18501694) (less)
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Pathogenic
(Dec 04, 2014)
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no assertion criteria provided
Method: literature only
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CATEL-MANZKE SYNDROME
Affected status: not provided
Allele origin:
germline
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OMIM
Accession: SCV000196644.2
First in ClinVar: Jan 17, 2015 Last updated: Jan 17, 2015 |
Comment on evidence:
In 3 patients with Catel-Manzke syndrome (616145), including the original patient described by Catel (1961) and 2 German girls reported by Manzke et al. (2008), … (more)
In 3 patients with Catel-Manzke syndrome (616145), including the original patient described by Catel (1961) and 2 German girls reported by Manzke et al. (2008), Ehmke et al. (2014) identified homozygosity for a c.298G-T transversion in the TGDS gene, resulting in an ala100-to-ser (A100S) substitution at a highly conserved residue in the NAD-binding domain. In 3 more unrelated patients with Catel-Manzke syndrome, Ehmke et al. (2014) identified the A100S mutation in compound heterozygosity with another missense mutation in the TGDS gene (616146.0002-616146.0004). A100S (rs140430952) was observed in heterozygous state in 9 of 4,300 controls in the NHLBI Exome Sequencing Project database and in 40 of 60,377 individuals analyzed by the Exome Aggregation Consortium. Using 10 informative markers, Ehmke et al. (2014) reconstructed a 50-kb haplotype shared by all individuals carrying the A100S allele, supporting the hypothesis of a founder mutation. (less)
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Pathogenic
(Dec 24, 2023)
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no assertion criteria provided
Method: clinical testing
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TGDS-related condition
Affected status: unknown
Allele origin:
germline
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PreventionGenetics, part of Exact Sciences
Accession: SCV004118257.3
First in ClinVar: Nov 20, 2023 Last updated: Oct 08, 2024 |
Comment:
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 … (more)
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. This variant is interpreted as pathogenic. (less)
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Pathogenic
(Sep 25, 2020)
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no assertion criteria provided
Method: clinical testing
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Catel-Manzke syndrome
Affected status: yes
Allele origin:
unknown
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Equipe Genetique des Anomalies du Developpement, Université de Bourgogne
Accession: SCV001439349.1
First in ClinVar: Oct 31, 2020 Last updated: Oct 31, 2020 |
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Germline Functional Evidence
| There is no functional evidence in ClinVar for this variation. If you have generated functional data for this variation, please consider submitting that data to ClinVar. |
Citations for germline classification of this variant
Help| Title | Author | Journal | Year | Link |
|---|---|---|---|---|
| Catel-Manzke syndrome without Manzke dysostosis. | Miller DE | American journal of medical genetics. Part A | 2020 | PMID: 31833187 |
| TGDS pathogenic variants cause Catel-Manzke syndrome without hyperphalangy. | Boschann F | American journal of medical genetics. Part A | 2020 | PMID: 31769200 |
| Mutations in TGDS associated with additional malformations of the middle fingers and halluces: Atypical Catel-Manzke syndrome in a fetus. | Schoner K | American journal of medical genetics. Part A | 2017 | PMID: 28422407 |
| Catel-Manzke Syndrome: Further Delineation of the Phenotype Associated with Pathogenic Variants in TGDS. | Pferdehirt R | Molecular genetics and metabolism reports | 2015 | PMID: 26366375 |
| Homozygous and compound-heterozygous mutations in TGDS cause Catel-Manzke syndrome. | Ehmke N | American journal of human genetics | 2014 | PMID: 25480037 |
| Catel-Manzke syndrome: two new patients and a critical review of the literature. | Manzke H | European journal of medical genetics | 2008 | PMID: 18501694 |
| Catel, W. Differentialdiagnose von Krankheitssymptomen bei Kindern und Jugendlichen. Vol. 1. (3rd ed.) Stuttgart: G. Thieme (pub.) 218-220, 1961. | - | - | - | - |
Text-mined citations for rs140430952 ...
HelpRecord last updated Nov 10, 2024
This date represents the last time this VCV record was updated. The update may be due to an update to one of the included submitted records (SCVs), or due to an update that ClinVar made to the variant such as adding HGVS expressions or a rs number. So this date may be different from the date of the “most recent submission” reported at the top of this page.