Submissions for variant NM_144991.3(TSPEAR):c.1915G>A (p.Asp639Asn)

gnomAD frequency: 0.00244  dbSNP: rs138480801

Total submissions: 16

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000218316	SCV000269929	benign	not specified	2016-01-07	criteria provided, single submitter	clinical testing	p.Asp639Asn in exon 12 of TSPEAR: This variant is not expected to have clinical significance because it has been identified in 0.5% (214/39556) of European chro mosomes by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.or g; dbSNP rs138480801).
GeneDx	RCV000844249	SCV000986296	pathogenic	not provided	2024-04-01	criteria provided, single submitter	clinical testing	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: 30046887, 27736875, 34042254, 25855803, 33144682, 37853563, 37009414)
Labcorp Genetics (formerly Invitae), Labcorp	RCV000844249	SCV001035626	likely benign	not provided	2024-01-05	criteria provided, single submitter	clinical testing
Athena Diagnostics	RCV000844249	SCV001146262	benign	not provided	2019-08-06	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV001267478	SCV001445659	uncertain significance	Inborn genetic diseases	2018-08-16	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV001335431	SCV001528581	uncertain significance	Autosomal recessive nonsyndromic hearing loss 98	2018-01-18	criteria provided, single submitter	clinical testing	This variant was determined to be of uncertain significance according to ACMG Guidelines, 2015 [PMID:25741868].
Duke University Health System Sequencing Clinic, Duke University Health System	RCV000721121	SCV003919029	likely pathogenic	Ectodermal dysplasia 14, hair/tooth type with or without hypohidrosis	2023-04-20	criteria provided, single submitter	research
CeGaT Center for Human Genetics Tuebingen	RCV000844249	SCV004146670	likely benign	not provided	2023-03-01	criteria provided, single submitter	clinical testing	TSPEAR: BS2
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	RCV000721121	SCV005086110	uncertain significance	Ectodermal dysplasia 14, hair/tooth type with or without hypohidrosis	2024-09-20	criteria provided, single submitter	clinical testing	Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as VUS-3A. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with tooth agenesis, selective, 10 (MIM#620173) and ectodermal dysplasia 14, hair/tooth type with or without hypohidrosis (MIM#618180). (I) 0106 - This gene is associated with autosomal recessive disease. (I) 0200 - Variant is predicted to result in a missense amino acid change from aspartic acid to asparagine. (I) 0252 - This variant is homozygous. (I) 0304 - Variant is present in gnomAD (v2) <0.01 for a recessive condition (592 heterozygotes, 1 homozygote). (SP) 0502 - Missense variant with conflicting in silico predictions and uninformative conservation. (I) 0604 - Variant is not located in an established domain, motif, hotspot or informative constraint region. (I) 0705 - No comparable missense variants have previous evidence for pathogenicity. (I) 0802 - This variant has moderate previous evidence of pathogenicity in unrelated individuals. This variant has been classified as benign, likely benign, a VUS and pathogenic by clinical laboratories in ClinVar. The variant has also been observed as compound heterozygous or homozygous in eight families with hypodontia and ectodermal dysplasia in the literature, and was classified as a VUS or as likely pathogenic (PMID: 34042254, 27736875, 37009414). (SP) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign
Pittsburgh Clinical Genomics Laboratory, University of Pittsburgh Medical Center	RCV000721121	SCV005397471	likely 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 (G>A) at coding nucleotide 1915 in the TSPEAR gene which results in an aspartic acid to asparagine amino acid change at residue 639 in the TSPEAR protein. This is a previously reported variant (ClinVar) which has been reported with a second variant in compound heterozygous state in multiple individuals with ectodermal dysplasia with tooth agenesis (PMID: 34042254, 27736875). The variant is present in 594/263832 alleles, including 1 homozygote, in the gnomAD control population dataset. Multiple bioinformatic tools predict that this variant is likely to be damaging, and aspartic acid is highly conserved at this protein position in vertebrates. Functiol studies testing the effects of this variant have not been performed, to our knowledge. Based on the available evidence, we consider this variant to be likely pathogenic; however, based on the presence of a homozygous individual in a control dataset, it may represent an allele which requires a stronger loss of function allele on the opposite chromosome for disease phenotypes to manifest. ACMG Criteria: PM3, PP3, PP4, PS4
OMIM	RCV000721121	SCV000852003	pathogenic	Ectodermal dysplasia 14, hair/tooth type with or without hypohidrosis	2022-12-05	no assertion criteria provided	literature only
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	RCV000844249	SCV001963134	uncertain significance	not provided		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV000844249	SCV001971025	uncertain significance	not provided		no assertion criteria provided	clinical testing
OMIM	RCV002470820	SCV002769559	pathogenic	Tooth agenesis, selective, 10	2022-12-20	no assertion criteria provided	literature only
Zotz-Klimas Genetics Lab, MVZ Zotz Klimas	RCV002470820	SCV004171618	uncertain significance	Tooth agenesis, selective, 10	2023-11-24	no assertion criteria provided	clinical testing
PreventionGenetics, part of Exact Sciences	RCV003977608	SCV004792731	likely benign	TSPEAR-related disorder	2020-08-24	no assertion criteria provided	clinical testing	This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications).