Submissions for variant NM_001283009.2(RTEL1):c.1877A>G (p.Lys626Arg)

gnomAD frequency: 0.00001  dbSNP: rs1018679403

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV001317319	SCV001507976	uncertain significance	Dyskeratosis congenita, autosomal recessive 5; Pulmonary fibrosis and/or bone marrow failure, Telomere-related, 3	2022-09-22	criteria provided, single submitter	clinical testing	This sequence change replaces lysine, which is basic and polar, with arginine, which is basic and polar, at codon 626 of the RTEL1 protein (p.Lys626Arg). This variant is present in population databases (no rsID available, gnomAD 0.006%). This variant has not been reported in the literature in individuals affected with RTEL1-related conditions. ClinVar contains an entry for this variant (Variation ID: 1018071). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Tolerated"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. 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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV003387992	SCV004100093	uncertain significance	not specified	2023-09-22	criteria provided, single submitter	clinical testing	Variant summary: RTEL1 c.1949A>G (p.Lys650Arg) results in a conservative amino acid change located in the ATP-dependent helicase, C-terminal domain (IPR006555) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. Several computational tools predict a significant impact on normal splicing: Four predict the variant weakens a canonical 5' donor site. One predicts the variant creates a cryptic 3' acceptor site and one predicts the variant strengthens this site. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 8.1e-06 in 246330 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. To our knowledge, no occurrence of c.1949A>G in individuals affected with Dyskeratosis Congenita (Hoyeraal Hreidarsson Syndrome) and no experimental evidence demonstrating its impact on protein function have been reported. Three submitters have cited clinical-significance assessments for this variant to ClinVar after 2014, and classified the variant as uncertain significance (n=2) or as a likely risk allele (n=1). Based on the evidence outlined above, the variant was classified as uncertain significance.
Breakthrough Genomics, Breakthrough Genomics	RCV004692479	SCV005195083	uncertain significance	not provided		criteria provided, single submitter	not provided
Natera, Inc.	RCV001835578	SCV002095438	uncertain significance	Dyskeratosis congenita	2020-02-21	no assertion criteria provided	clinical testing
Garcia Pulmonary Genetics Research Laboratory, Columbia University Irving Medical Center	RCV002509660	SCV002547369	likely risk allele	Pulmonary fibrosis	2022-06-09	no assertion criteria provided	research	Leukocyte telomere length (by qPCR) less than 10th percentile age-adjusted