Submissions for variant NM_001283009.2(RTEL1):c.396-37C>T

gnomAD frequency: 0.00322  dbSNP: rs41297642

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Genetic Services Laboratory, University of Chicago	RCV000501044	SCV000596806	benign	not specified	2021-04-29	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV000651108	SCV000772958	likely benign	Dyskeratosis congenita, autosomal recessive 5; Pulmonary fibrosis and/or bone marrow failure, Telomere-related, 3	2024-01-18	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV002329201	SCV002627733	likely benign	Inborn genetic diseases	2022-10-04	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.
CeGaT Center for Human Genetics Tuebingen	RCV003431052	SCV004150971	likely benign	not provided	2023-09-01	criteria provided, single submitter	clinical testing	RTEL1: BP4, BS2
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000501044	SCV005204157	likely benign	not specified	2024-06-20	criteria provided, single submitter	clinical testing	Variant summary: RTEL1 c.431C>T (p.Thr144Ile) results in a non-conservative amino acid change located in the Helicase-like, DEXD box c2 type domain (IPR006554) of the encoded protein sequence. Two of three in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.0027 in 245238 control chromosomes, predominantly at a frequency of 0.0053 within the Non-Finnish European subpopulation in the gnomAD database, including 2 homozygotes. The observed variant frequency within Non-Finnish European control individuals in the gnomAD database is approximately 4.74 fold of the estimated maximal expected allele frequency for a pathogenic variant in RTEL1 causing Dyskeratosis Congenita (Hoyeraal Hreidarsson Syndrome) phenotype (0.0011). c.431C>T has been reported in the literature in 5 individuals affected with Chronic obstructive pulmonary disease and 2 controls (Qiao_2018). These report(s) do not provide unequivocal conclusions about association of the variant with Dyskeratosis Congenita (Hoyeraal Hreidarsson Syndrome). To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publication have been ascertained in the context of this evaluation (PMID: 30060175). ClinVar contains an entry for this variant (Variation ID: 436561). Based on the evidence outlined above, the variant was classified as likely benign.
Breakthrough Genomics, Breakthrough Genomics	RCV003431052	SCV005210164	likely benign	not provided		criteria provided, single submitter	not provided
Natera, Inc.	RCV001834614	SCV002095362	benign	Dyskeratosis congenita	2019-12-08	no assertion criteria provided	clinical testing
PreventionGenetics, part of Exact Sciences	RCV004535613	SCV004732091	likely benign	RTEL1-related disorder	2020-08-31	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).