Submissions for variant NM_016233.2(PADI3):c.335T>A (p.Leu112His)

gnomAD frequency: 0.00502  dbSNP: rs142129409

Total submissions: 13

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV001528551	SCV001983056	pathogenic	not provided	2025-01-16	criteria provided, single submitter	clinical testing	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, 35751533, 36044230, 36541401, 36920900)
Mendelics	RCV000415522	SCV002517840	pathogenic	Uncombable hair syndrome 1	2022-05-04	criteria provided, single submitter	clinical testing
Genetics and Molecular Pathology, SA Pathology	RCV000415522	SCV002556712	pathogenic	Uncombable hair syndrome 1	2021-05-31	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV001528551	SCV002562899	likely pathogenic	not provided	2023-10-01	criteria provided, single submitter	clinical testing	PADI3: PM3:Very Strong, PM2:Supporting
Greenwood Genetic Center Diagnostic Laboratories, Greenwood Genetic Center	RCV000415522	SCV004099173	pathogenic	Uncombable hair syndrome 1	2023-09-25	criteria provided, single submitter	clinical testing	PS3, PM3_Strong, PP3
Genomic Medicine Center of Excellence, King Faisal Specialist Hospital and Research Centre	RCV000415522	SCV004806942	likely pathogenic	Uncombable hair syndrome 1	2024-03-26	criteria provided, single submitter	clinical testing
OMIM	RCV000415522	SCV000493954	pathogenic	Uncombable hair syndrome 1	2019-03-07	no assertion criteria provided	literature only
Reproductive Health Research and Development, BGI Genomics	RCV000415522	SCV001142291	pathogenic	Uncombable hair syndrome 1	2020-01-06	no assertion criteria provided	curation	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.
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	RCV001528551	SCV001740445	likely pathogenic	not provided		no assertion criteria provided	clinical testing
Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	RCV001528551	SCV001797595	pathogenic	not provided		no assertion criteria provided	clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV001528551	SCV001959750	likely pathogenic	not provided		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV001528551	SCV001980655	likely pathogenic	not provided		no assertion criteria provided	clinical testing
PreventionGenetics, part of Exact Sciences	RCV003409583	SCV004113516	pathogenic	PADI3-related disorder	2024-06-20	no assertion criteria provided	clinical testing	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.