ClinVar Genomic variation as it relates to human health
NM_016233.2(PADI3):c.335T>A (p.Leu112His)
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_016233.2(PADI3):c.335T>A (p.Leu112His)
Variation ID: 374868 Accession: VCV000374868.36
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 1p36.13 1: 17262194 (GRCh38) [ NCBI UCSC ] 1: 17588689 (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 Mar 10, 2019 Oct 8, 2024 Jun 10, 2024 - HGVS
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Nucleotide Protein Molecular
consequenceNM_016233.2:c.335T>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_057317.2:p.Leu112His missense NC_000001.11:g.17262194T>A NC_000001.10:g.17588689T>A NG_052788.1:g.18116T>A - Protein change
- L112H
- Other names
- -
- Canonical SPDI
- NC_000001.11:17262193:T: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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0.00240 (A)
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Allele frequency
Help
The frequency of the allele represented by this VCV record.
1000 Genomes Project 0.00240
1000 Genomes Project 30x 0.00250
Exome Aggregation Consortium (ExAC) 0.00412
The Genome Aggregation Database (gnomAD), exomes 0.00455
The Genome Aggregation Database (gnomAD) 0.00502
NHLBI Exome Sequencing Project (ESP) Exome Variant Server 0.00523
Trans-Omics for Precision Medicine (TOPMed) 0.00540
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
Help
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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PADI3 | - | - |
GRCh38 GRCh38 GRCh37 |
96 | 120 |
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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Mar 26, 2024 | RCV000415522.11 | |
Pathogenic/Likely pathogenic (6) |
criteria provided, multiple submitters, no conflicts
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Jun 10, 2024 | RCV001528551.25 | |
PADI3-related disorder
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Pathogenic (1) |
no assertion criteria provided
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Jun 20, 2024 | RCV003409583.6 |
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
(May 04, 2022)
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criteria provided, single submitter
Method: clinical testing
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Uncombable hair syndrome 1
Affected status: unknown
Allele origin:
germline
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Mendelics
Accession: SCV002517840.1
First in ClinVar: May 28, 2022 Last updated: May 28, 2022 |
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Pathogenic
(May 31, 2021)
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criteria provided, single submitter
Method: clinical testing
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Uncombable hair syndrome 1
Affected status: yes
Allele origin:
germline
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Genetics and Molecular Pathology, SA Pathology
Additional submitter:
Shariant Australia, Australian Genomics
Accession: SCV002556712.2
First in ClinVar: Aug 04, 2022 Last updated: Dec 17, 2022 |
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Pathogenic
(Sep 25, 2023)
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criteria provided, single submitter
Method: clinical testing
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Uncombable hair syndrome 1
Affected status: yes
Allele origin:
germline
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Greenwood Genetic Center Diagnostic Laboratories, Greenwood Genetic Center
Accession: SCV004099173.1
First in ClinVar: Oct 28, 2023 Last updated: Oct 28, 2023 |
Comment:
PS3, PM3_Strong, PP3
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Likely pathogenic
(Mar 26, 2024)
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criteria provided, single submitter
Method: clinical testing
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Uncombable hair syndrome 1
Affected status: unknown
Allele origin:
germline
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Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center
Accession: SCV004806942.1
First in ClinVar: Apr 06, 2024 Last updated: Apr 06, 2024 |
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Pathogenic
(Jun 10, 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: SCV001983056.5
First in ClinVar: Oct 30, 2021 Last updated: Sep 29, 2024 |
Comment:
Published functional studies demonstrate a damaging effect; specifically, the L112H variant is associated with absent enzyme activity and abnormal enzyme aggregation (PMID: 27866708); In silico … (more)
Published functional studies demonstrate a damaging effect; specifically, the L112H variant is associated with absent enzyme activity and abnormal enzyme aggregation (PMID: 27866708); 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: 31952341, 27866708, 34426522, 34297361, 36044230, 36541401, 36920900, 35751533) (less)
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Likely pathogenic
(Oct 01, 2023)
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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: SCV002562899.15
First in ClinVar: Aug 23, 2022 Last updated: Oct 08, 2024 |
Comment:
PADI3: PM3:Very Strong, PM2:Supporting
Number of individuals with the variant: 3
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Pathogenic
(Mar 07, 2019)
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no assertion criteria provided
Method: literature only
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UNCOMBABLE HAIR SYNDROME 1
Affected status: not provided
Allele origin:
germline
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OMIM
Accession: SCV000493954.2
First in ClinVar: Jan 23, 2017 Last updated: Mar 10, 2019 |
Comment on evidence:
By Sanger sequencing of the PADI3 gene in 17 patients with uncombable hair syndrome (UHS1; 191480), U. Basmanav et al. (2016) identified a c.335T-A transversion … (more)
By Sanger sequencing of the PADI3 gene in 17 patients with uncombable hair syndrome (UHS1; 191480), U. Basmanav et al. (2016) identified a c.335T-A transversion (rs142129409), resulting in a leu112-to-his (L112H) substitution at a conserved residue, in homozygous or compound heterozygous state in 5 patients. The L112H mutation was predicted to affect the 3-dimensional structure of the protein: modifications of beta sheets and alpha helices, in particular in the Ig-like NH2 domains, and also around the catalytic site and the calcium-binding site. Immunofluorescence studies in HaCaT cells showed a diffuse homogeneous cytoplasmic distribution of wildtype PADI3, whereas the mutant protein formed large aggregates throughout the cytoplasm. Additional studies suggested that the mutant form was either not or only weakly active. The L112H variant was not found in homozygosity in the ExAC database. (less)
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Pathogenic
(Jan 06, 2020)
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no assertion criteria provided
Method: curation
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Uncombable hair syndrome
Affected status: unknown
Allele origin:
germline
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Reproductive Health Research and Development, BGI Genomics
Accession: SCV001142291.1
First in ClinVar: Jan 12, 2020 Last updated: Jan 12, 2020 |
Comment:
NM_016233.2:c.335T>A in the PADI3 gene has an allele frequency of 0.007 in European(non-Finnish) subpopulation in the gnomAD database. Functional studies demonstrate that c.335T>A has affected … (more)
NM_016233.2:c.335T>A in the PADI3 gene has an allele frequency of 0.007 in European(non-Finnish) subpopulation in the gnomAD database. Functional studies demonstrate that c.335T>A has affected transglutaminase activity of TGM3 produced in HEK293T cells (PMID: 27866708). It was detected in multiple individuals with autosomal recessive Uncombable hair syndrome, homozygous c.335T>A, compound heterozygous with c.1813C>A, and c.881C>T, respectively (PMID: 27866708). The patient's phenotype is highly specific for PADI3 gene(PMID:27866708). Pathogenic computational verdict because pathogenic predictions from DANN, EIGEN, FATHMM-MKL, M-CAP, MutationAssessor. Taken together, we interprete this variant as Pathogenic/Likely pathogenic variant. ACMG/AMP criteria applied: PS3; PM3_Strong; PP4; PP3. (less)
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Pathogenic
(-)
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no assertion criteria provided
Method: clinical testing
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not provided
Affected status: yes
Allele origin:
germline
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Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)
Study: VKGL Data-share Consensus
Accession: SCV001797595.1 First in ClinVar: Aug 21, 2021 Last updated: Aug 21, 2021 |
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Likely pathogenic
(-)
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no assertion criteria provided
Method: clinical testing
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not provided
Affected status: yes
Allele origin:
germline
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Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen
Study: VKGL Data-share Consensus
Accession: SCV001740445.3 First in ClinVar: Jul 07, 2021 Last updated: Sep 08, 2021 |
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Likely pathogenic
(-)
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no assertion criteria provided
Method: clinical testing
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not provided
Affected status: yes
Allele origin:
germline
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Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+
Additional submitter:
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen
Study: VKGL Data-share Consensus
Accession: SCV001959750.1 First in ClinVar: Oct 02, 2021 Last updated: Oct 02, 2021 |
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Likely pathogenic
(-)
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no assertion criteria provided
Method: clinical testing
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not provided
Affected status: yes
Allele origin:
germline
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Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center
Additional submitter:
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen
Study: VKGL Data-share Consensus
Accession: SCV001980655.1 First in ClinVar: Oct 16, 2021 Last updated: Oct 16, 2021 |
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Pathogenic
(Jun 20, 2024)
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no assertion criteria provided
Method: clinical testing
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PADI3-related condition
Affected status: unknown
Allele origin:
germline
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PreventionGenetics, part of Exact Sciences
Accession: SCV004113516.3
First in ClinVar: Nov 20, 2023 Last updated: Oct 08, 2024 |
Comment:
The PADI3 c.335T>A variant is predicted to result in the amino acid substitution p.Leu112His. This variant has been reported in the homozygous and compound heterozygous … (more)
The PADI3 c.335T>A variant is predicted to result in the amino acid substitution p.Leu112His. This variant has been reported in the homozygous and compound heterozygous states with another variant [c.881C>T (p.Ala294Val)] to be causative for autosomal recessive uncombable hair syndrome in several unrelated patients (Basmanav et al. 2016. PubMed ID: 27866708; OMIM #191480). This variant is reported in 0.70% of alleles in individuals of European (Non-Finnish) descent in gnomAD. In summary, we classify this variant as pathogenic. (less)
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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
HelpTitle | Author | Journal | Year | Link |
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Mutations in Three Genes Encoding Proteins Involved in Hair Shaft Formation Cause Uncombable Hair Syndrome. | Ü Basmanav FB | American journal of human genetics | 2016 | PMID: 27866708 |
Text-mined citations for rs142129409 ...
HelpRecord last updated Oct 13, 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.