Submissions for variant NM_144991.3(TSPEAR):c.589C>T (p.Arg197Ter)

gnomAD frequency: 0.00027  dbSNP: rs139455627

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Undiagnosed Diseases Network, NIH	RCV000708577	SCV000837699	likely pathogenic	TSPEAR-related disorder of tooth and hair follicle morphogenesis	2018-06-25	criteria provided, single submitter	clinical testing
GeneDx	RCV000760528	SCV000890419	pathogenic	not provided	2024-10-04	criteria provided, single submitter	clinical testing	Observed multiple times with another TSPEAR variant in unrelated patients in published literature with ectodermal dysplasia or oligodontia, but it is not known whether the variants occurred on the same (in cis) or on different (in trans) chromosomes in some cases (PMID: 34042254, 37009414); Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; This variant is associated with the following publications: (PMID: 27736875, 33144682, 37009414, 34042254)
Ambry Genetics	RCV001266951	SCV001445132	pathogenic	Inborn genetic diseases	2019-03-28	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV000760528	SCV002297661	pathogenic	not provided	2025-01-21	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Arg197*) in the TSPEAR gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in TSPEAR are known to be pathogenic (PMID: 34042254). This variant is present in population databases (rs139455627, gnomAD 0.06%). This premature translational stop signal has been observed in individuals with clinical features of ectodermal dysplasia (PMID: 34042254; internal data). This variant is also known as c.385C>T, p.Arg129*. ClinVar contains an entry for this variant (Variation ID: 403572). For these reasons, this variant has been classified as Pathogenic.
MGZ Medical Genetics Center	RCV002289583	SCV002579448	pathogenic	Ectodermal dysplasia 14, hair/tooth type with or without hypohidrosis	2021-09-21	criteria provided, single submitter	clinical testing
Pittsburgh Clinical Genomics Laboratory, University of Pittsburgh Medical Center	RCV002289583	SCV005397470	pathogenic	Ectodermal dysplasia 14, hair/tooth type with or without hypohidrosis	2022-08-03	criteria provided, single submitter	clinical testing	This sequence variant is a single nucleotide substitution (C>T) at coding nucleotide 589 in the TSPEAR gene which changes the arginine 197 codon into an early termition sigl. As it occurs in exon 4 of 12, this variant is predicted to generate a non-functiol allele through the expression of a truncated protein or a loss of TSPEAR expression due to nonsense-mediated decay. This is a previously reported variant (ClinVar) which has been observed with a second variant in multiple individuals with ectodermal dysplasia with and without tooth agenesis (PMID: 34042254). This variant is present in 86 of 281928 alleles (0.03%) in the gnomAD control population dataset. Given the data, we consider this variant to be pathogenic. ACMG Criteria: PM3, PP4, PVS1
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000455938	SCV000540611	uncertain significance	not specified	2016-04-25	flagged submission	clinical testing	Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: One frameshift variant in the gene has been reported in a consanguineous family with AR deafness (Delmaghani 2012). Variant segregated in 2 affected siblings. Variant disrupts protein function when transfected into cells in vitro. Limited evidence for gene's association with disease. Does not meet criteria for reporting in BabySeq.
PreventionGenetics, part of Exact Sciences	RCV003418147	SCV004114433	pathogenic	TSPEAR-related disorder	2024-06-21	no assertion criteria provided	clinical testing	The TSPEAR c.589C>T variant is predicted to result in premature protein termination (p.Arg197*). This variant, also reported as c.385C>T (p.Arg129*) using a different transcript (NM_001272037.1), has been reported in the homozygous and compound heterozygous states in individuals with TSPEAR-related disorders (Klee et al. 2021. PubMed ID: 33144682; Bowles et al. 2021. PubMed ID: 34042254; Jackson et al. 2023. PubMed ID: 37009414). This variant is reported in 0.059% of alleles in individuals of European (Non-Finnish) descent in gnomAD. Nonsense variants in TSPEAR are expected to be pathogenic. This variant is interpreted as pathogenic.