Submissions for variant NM_001283009.2(RTEL1):c.718A>G (p.Ile240Val)

gnomAD frequency: 0.00010  dbSNP: rs141578937

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV001242645	SCV001415747	uncertain significance	Dyskeratosis congenita, autosomal recessive 5; Pulmonary fibrosis and/or bone marrow failure, Telomere-related, 3	2022-10-25	criteria provided, single submitter	clinical testing	This sequence change replaces isoleucine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 240 of the RTEL1 protein (p.Ile240Val). This variant is present in population databases (rs141578937, gnomAD 0.02%). This variant has not been reported in the literature in individuals affected with RTEL1-related conditions. This variant is also known as c.790A>G (p.Ile264Val). ClinVar contains an entry for this variant (Variation ID: 967672). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Sema4, Sema4	RCV001835134	SCV002535806	uncertain significance	Dyskeratosis congenita	2022-02-23	criteria provided, single submitter	curation
Ambry Genetics	RCV004671294	SCV005161508	uncertain significance	Inborn genetic diseases	2024-05-07	criteria provided, single submitter	clinical testing	The c.790A>G (p.I264V) alteration is located in exon 9 (coding exon 8) of the RTEL1 gene. This alteration results from a A to G substitution at nucleotide position 790, causing the isoleucine (I) at amino acid position 264 to be replaced by a valine (V). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear.
GeneDx	RCV004720813	SCV005327388	uncertain significance	not provided	2023-11-05	criteria provided, single submitter	clinical testing	In silico analysis supports that this missense variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge; This variant is associated with the following publications: (PMID: 26740555, 28719003)
Pittsburgh Clinical Genomics Laboratory, University of Pittsburgh Medical Center	RCV004783936	SCV005397372	uncertain significance	Pulmonary fibrosis and/or bone marrow failure, Telomere-related, 3	2023-09-08	criteria provided, single submitter	clinical testing	This sequence variant is a single nucleotide substitution (A>G) at position 718 of the coding sequence of the RTEL1 gene that results in an isoleucine to valine amino acid change at residue 240 of the regulator of telomere elongation helicase 1 protein. Residue 240 falls in the first helicase domain (PMID: 26022962) which plays a critical role telomere maintence. This is a previously reported variant (ClinVar 967672) that has not been observed in individuals affected by a RTEL1-related disorder in the published literature, to our knowledge. This variant is present in 30 of 238732 alleles (0.0126%) in the gnomAD population dataset. Multiple bioinformatic tools predict that this isoleucine to valine amino acid change would be neutral, and the isoleucine residue at this position is highly conserved across the vertebrate species examined. Studies examining the functiol consequence of this variant have not been published, to our knowledge. Based upon the evidence, we consider this a variant of uncertain significance. ACMG Criteria: BP4
Natera, Inc.	RCV001835134	SCV002095381	uncertain significance	Dyskeratosis congenita	2021-01-21	no assertion criteria provided	clinical testing