ClinVar Miner

Submissions for variant NM_032957.4(RTEL1):c.2941C>T (p.Arg981Trp) (rs398123018)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000588014 SCV000699749 likely pathogenic Dyskeratosis congenita 2016-06-16 criteria provided, single submitter clinical testing Variant summary:The RTEL1 c.2941C>T (p.Arg981Trp) variant involves the alteration of a conserved nucleotide. 4/4 in silico tools predict a damaging outcome for this variant. This variant lies in less-defined harmonin N-like/PAH helical fold domain that could potentially form a hub for interaction with partner proteins (Vannier_2015). This variant was found in 6/119930 control chromosomes at a frequency of 0.00005, which does not exceed the estimated maximal expected allele frequency of a pathogenic RTEL1 variant (0.001118). This variant has been reported in three unrelated probands affected with Dyskeratosis Congenita in compound heterozygous with other potentially pathogenic variants, strongly suggesting for likely pathogenic outcome (Walne_2013). Patient cells from those patients showed significant defects in telomere maintenance, further supporting the pathogenic outcome. Two reputable databases have classified it as pathogenic. Taken together, this variant is currently classified as Likely Pathogenic.
Invitae RCV001239040 SCV001411885 uncertain significance Dyskeratosis congenita, autosomal recessive, 5; Pulmonary fibrosis and/or bone marrow failure, telomere-related, 3 2020-10-03 criteria provided, single submitter clinical testing This sequence change replaces arginine with tryptophan at codon 957 of the RTEL1 protein (p.Arg957Trp). The arginine residue is moderately conserved and there is a moderate physicochemical difference between arginine and tryptophan. This variant is present in population databases (rs398123018, ExAC 0.02%). This variant has been observed in individuals and families affected with dyskeratosis congenita (PMID: 23453664). This variant is also known as c.2941C>T (p.Arg981Trp) in the literature. ClinVar contains an entry for this variant (Variation ID: 42021). 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: Deleterious; PolyPhen-2: Probably Damaging; Align-GVGD: Class C0). 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.
OMIM RCV000034863 SCV000058467 pathogenic Dyskeratosis congenita, autosomal recessive, 5 2013-03-07 no assertion criteria provided literature only
Counsyl RCV000034863 SCV000789497 likely pathogenic Dyskeratosis congenita, autosomal recessive, 5 2017-02-02 no assertion criteria provided clinical testing
Natera, Inc. RCV000588014 SCV001456916 likely pathogenic Dyskeratosis congenita 2020-09-16 no assertion criteria provided clinical testing

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