Submissions for variant NM_016233.2(PADI3):c.881C>T (p.Ala294Val)

gnomAD frequency: 0.00620  dbSNP: rs144080386

Total submissions: 11

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV001702455	SCV001982998	pathogenic	not provided	2022-06-19	criteria provided, single submitter	clinical testing	Published functional studies demonstrate a damaging effect; specifically, the A294V variant is associated with decreased enzyme activity and abnormal enzyme aggregation (Basmanav et al., 2016).; 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: 29756256, 22381266, 27866708, 31952341, 34426522, 35279260, 24629392)
Mendelics	RCV000415579	SCV002518429	pathogenic	Uncombable hair syndrome 1	2024-09-24	criteria provided, single submitter	clinical testing	The PADI3 c.881C>T (p.Ala294Val) variant (rs144080386) is cited by previous literature (Basmanav et al. 2016. PubMed ID 27866708). This variant is reported as pathogenic by laboratories in ClinVar (Variation ID: 374867). GnomAD 4.1.0 frequency is 0.007561 with 62 homozygotes. It is an OMIM variant: https://omim.org/entry/606755#0001. Prediction of the impact of the variant on the resulting protein and immunofluorescence studies were performed by Basmanav et al. 2016 with results coherent with modified function.
Genetics and Molecular Pathology, SA Pathology	RCV000415579	SCV002557030	pathogenic	Uncombable hair syndrome 1	2021-05-31	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV001702455	SCV004123321	likely pathogenic	not provided	2023-10-01	criteria provided, single submitter	clinical testing	PADI3: PM3:Very Strong, PM2:Supporting
OMIM	RCV000415579	SCV000493953	pathogenic	Uncombable hair syndrome 1	2022-05-25	no assertion criteria provided	literature only
Reproductive Health Research and Development, BGI Genomics	RCV000415579	SCV001142292	pathogenic	Uncombable hair syndrome 1	2020-01-06	no assertion criteria provided	curation	NM_016233.2:c.881C>T in the PADI3 gene has an allele frequency of 0.017 in Ashkenazi Jewish subpopulation in the gnomAD database. Functional studies demonstrate that c.881C>T 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.881C> T(p.Ala294Val), compound heterozygous with c.335T>A (p.Leu112His) ,c.1732A>T (p.Lys578*)(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, MutationAssessor, MutationTaster and SIFT. Taken together, we interprete this variant as Pathogenic/Likely pathogenic variant. ACMG/AMP criteria applied: PS3; PM3_Strong; PP4; PP3.
Genome Diagnostics Laboratory, University Medical Center Utrecht	RCV001702455	SCV001928240	pathogenic	not provided		no assertion criteria provided	clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV001702455	SCV001954292	pathogenic	not provided		no assertion criteria provided	clinical testing
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	RCV001702455	SCV001963578	pathogenic	not provided		no assertion criteria provided	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV001702455	SCV004445944	benign	not provided	2024-01-05	flagged submission	clinical testing
PreventionGenetics, part of Exact Sciences	RCV003932540	SCV004751003	pathogenic	PADI3-related disorder	2024-09-27	no assertion criteria provided	clinical testing	The PADI3 c.881C>T variant is predicted to result in the amino acid substitution p.Ala294Val. This variant has been reported in both the homozygous and heterozygous states as causative for uncombable hair syndrome in several patients (Basmanav et al. 2016. PubMed ID: 27866708; Drivenes et al. 2022. PubMed ID: 35279260). This variant was observed in a public database with allele frequency up to ~0.90% in European populations and 1.75% in Ashkenazi Jewish populations, respectively; 15 homozygotes of this variant were also reported out of 282,758 alleles. Although this variant is common in the general population, it is classified as pathogenic.