Submissions for variant NM_001010874.5(TECRL):c.893T>C (p.Val298Ala)

gnomAD frequency: 0.00093  dbSNP: rs146610448

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV001779614	SCV002015312	uncertain significance	not provided	2021-07-27	criteria provided, single submitter	clinical testing	Reported in a patient with syncope and arrhythmia who also harbors a nonsense variant in the TECRL gene (Marschall et al., 2019); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; This variant is associated with the following publications: (PMID: 31737537, 32173957)
Ambry Genetics	RCV002370316	SCV002687430	likely benign	Cardiovascular phenotype	2022-05-23	criteria provided, single submitter	clinical testing	This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	RCV002471152	SCV002767481	uncertain significance	Catecholaminergic polymorphic ventricular tachycardia 3	2022-03-31	criteria provided, single submitter	clinical testing	Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as VUS-3B. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with catecholaminergic polymorphic ventricular tachycardia 3 (CPVT; MIM#614021). (I) 0106 - This gene is associated with autosomal recessive disease. (I) 0115 - Variants in this gene are known to have variable expressivity (PMID: 32173957). (I) 0200 - Variant is predicted to result in a missense amino acid change from valine to alanine. (I) 0251 - This variant is heterozygous. (I) 0304 - Variant is present in gnomAD (v2) <0.01 for a recessive condition (257 heterozygotes, 0 homozygotes). (SP) 0502 - Missense variant with conflicting in silico predictions and uninformative conservation. (I) 0600 - Variant is located in the annotated 3-oxo-5-alpha steroid 4-dehydrogenase domain (DECIPHER, PMID: 32173957). (I) 0705 - No comparable missense variants have previous evidence for pathogenicity. (I) 0808 - Previous reports of pathogenicity for this variant are conflicting. This variant has been reported as a VUS (ClinVar, LOVD), and described in a compound heterozygous individual with long QT syndrome (LQTS) and CPVT. This individual's child also has features of LQTS but was only heterozygous for this variant (PMID: 32173957, PMID: 31737537). (I) 0905 - No published segregation evidence has been identified for this variant. (I) 1007 - No published functional evidence has been identified for this variant. (I) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV003155428	SCV003844861	uncertain significance	not specified	2025-02-10	criteria provided, single submitter	clinical testing	Variant summary: TECRL c.893T>C (p.Val298Ala) results in a non-conservative amino acid change located in the 3-oxo-5-alpha-steroid 4-dehydrogenase, C-terminal domain (IPR001104) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00094 in 245588 control chromosomes (gnomAD). This frequency is not significantly higher than estimated for a pathogenic variant in TECRL causing Catecholaminergic Polymorphic Ventricular Tachycardia (0.00094 vs 0.0025), allowing no conclusion about variant significance. c.893T>C has been reported in the literature in at least one compound heterozygous individual affected with Arrhythmia (Marschall_2019). These data do not allow any conclusion about variant significance. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 31737537, 32173957). ClinVar contains an entry for this variant (Variation ID: 1321522). Based on the evidence outlined above, the variant was classified as uncertain significance.
Mayo Clinic Laboratories, Mayo Clinic	RCV001779614	SCV005410546	uncertain significance	not provided	2024-01-11	criteria provided, single submitter	clinical testing	BS1
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV002471152	SCV005876589	uncertain significance	Catecholaminergic polymorphic ventricular tachycardia 3	2024-02-29	criteria provided, single submitter	clinical testing	The TECRL c.893T>C; p.Val298Ala variant (rs146610448) is reported in the literature in the compound heterozygous state with a different truncating variant in TECRL an individual affected with catecholaminergic polymorphic ventricular tachycardia (Moscu-Gregor 2020). This variant is also reported in ClinVar (Variation ID: 1321522), and is found in the general population with an overall allele frequency of 0.093% (257/276910 alleles) in the Genome Aggregation Database. The valine at codon 298 is highly conserved, and computational analyses are uncertain whether this variant is neutral or deleterious (REVEL: 0.478). Due to limited clinical data and a lack of functional data, the significance of this variant is uncertain at this time. References: Moscu-Gregor A et al. Novel variants in TECRL cause recessive inherited CPVT type 3 with severe and variable clinical symptoms. J Cardiovasc Electrophysiol. 2020 Jun;31(6):1527-1535. PMID: 32173957.
Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute	RCV002370316	SCV006070262	uncertain significance	Cardiovascular phenotype	2025-04-09	criteria provided, single submitter	clinical testing