Submissions for variant NM_001283009.2(RTEL1):c.1476G>T (p.Met492Ile)

gnomAD frequency: 0.00001  dbSNP: rs370343781

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000586033	SCV000699742	likely pathogenic	Dyskeratosis congenita	2016-06-16	criteria provided, single submitter	clinical testing	Variant summary: The RTEL1 c.1548G>T (p.Met516Ile) variant involves the alteration of a conserved nucleotide. 2/3 in silico tools used predict a damaging outcome. This variant was found in 2/35814 control chromosomes at a frequency of 0.0000558, which does not exceed the estimated maximal expected allele frequency of a pathogenic RTEL1 variant (0.001118). This variant has been detected in four affected siblings from a family who were compound heterozygous for this variant and R998X. The parents were carriers of either of the mutations and an unaffected grandfather carried this variant in heterozygous state. This family data is consistent with disease causing outcome of the variant. Functional studies using patient cells showed telomere shortening, increased senescence, and an increased frequency of telomere defects, such as fragile telomeres and signal-free ends, but no increase in pathogenic T-circle formation on 2D gel electrophoresis (Deng_2013). The same authors also showed minor changes in telomere length caused by the variant in vitro. Jalas (2013) reports the carrier frequency of this variant in AJ as 0.19%. Two reputable databases have classified this variant as pathogenic. Taken together, this variant is currently classified as a Probable Disease Variant (or Likely Pathogenic).
Labcorp Genetics (formerly Invitae), Labcorp	RCV000824065	SCV000964946	pathogenic	Dyskeratosis congenita, autosomal recessive 5; Pulmonary fibrosis and/or bone marrow failure, Telomere-related, 3	2024-04-10	criteria provided, single submitter	clinical testing	This sequence change replaces methionine, which is neutral and non-polar, with isoleucine, which is neutral and non-polar, at codon 492 of the RTEL1 protein (p.Met492Ile). This variant is present in population databases (rs370343781, gnomAD 0.09%). This missense change has been observed in individual(s) with Hoyeraal–Hreidarsson syndrome and myelodysplastic syndrome (PMID: 19461895, 23453664, 23959892, 27418648). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. It has also been observed to segregate with disease in related individuals. This variant is also known as c.1548G>T (p.Met516Ile). ClinVar contains an entry for this variant (Variation ID: 42019). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. Experimental studies have shown that this missense change affects RTEL1 function (PMID: 19461895, 23959892). This variant disrupts the p.Met492 amino acid residue in RTEL1. Other variant(s) that disrupt this residue have been observed in individuals with RTEL1-related conditions (PMID: 26808564), which suggests that this may be a clinically significant amino acid residue. For these reasons, this variant has been classified as Pathogenic.
Revvity Omics, Revvity	RCV003129760	SCV003812007	likely pathogenic	not provided	2022-03-10	criteria provided, single submitter	clinical testing
GeneDx	RCV003129760	SCV004169101	pathogenic	not provided	2023-11-10	criteria provided, single submitter	clinical testing	Published functional studies demonstrate telomere shortening, fragility and fusion, and growth defects (PMID: 23959892); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Also known as M492I; This variant is associated with the following publications: (PMID: 23453664, 27418648, 27415407, 19461895, 25047097, 23959892, 32561545, 32542379, 25940403)
Baylor Genetics	RCV000034861	SCV004209343	likely pathogenic	Dyskeratosis congenita, autosomal recessive 5	2024-03-21	criteria provided, single submitter	clinical testing
OMIM	RCV000034861	SCV000058465	pathogenic	Dyskeratosis congenita, autosomal recessive 5	2013-09-03	no assertion criteria provided	literature only