ClinVar Miner

Submissions for variant NM_032957.4(RTEL1):c.1548G>T (p.Met516Ile) (rs370343781)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Integrated Genetics/Laboratory Corporation of America 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).
Invitae RCV000824065 SCV000964946 pathogenic Dyskeratosis congenita, autosomal recessive, 5; Pulmonary fibrosis and/or bone marrow failure, telomere-related, 3 2019-09-26 criteria provided, single submitter clinical testing This sequence change replaces methionine with isoleucine at codon 492 of the RTEL1 protein (p.Met492Ile). The methionine residue is highly conserved and there is a small physicochemical difference between methionine and isoleucine. This variant is present in population databases (rs370343781, ExAC 0.05%). This variant has been observed to segregate with Hoyeraal Hreidarsson syndrome in a family (PMID: 23959892, 19461895, 23453664). It has also been observed in an individual with myelodysplastic syndrome (PMID: 27418648). This variant is also known as c.1548G>T (p.Met516Ile) in the literature. ClinVar contains an entry for this variant (Variation ID: 42019). Experimental studies have shown that this missense change disrupts RTEL1 protein function (PMID: 23959892, 19461895). This variant disrupts the p.Met492 (also known as p.Met516) amino acid residue in RTEL1. Other variant(s) that disrupt this residue have been observed in affected individuals (PMID: 26808564), which suggests that this may be a clinically significant amino acid residue. For these reasons, this variant has been classified as Pathogenic.
OMIM RCV000034861 SCV000058465 pathogenic Dyskeratosis congenita, autosomal recessive, 5 2013-09-03 no assertion criteria provided literature only

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