Submissions for variant NM_001283009.2(RTEL1):c.2470C>T (p.Pro824Ser)

gnomAD frequency: 0.00027  dbSNP: rs138188555

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV001241882	SCV001414934	uncertain significance	Dyskeratosis congenita, autosomal recessive 5; Pulmonary fibrosis and/or bone marrow failure, Telomere-related, 3	2022-10-23	criteria provided, single submitter	clinical testing	This sequence change replaces proline, which is neutral and non-polar, with serine, which is neutral and polar, at codon 824 of the RTEL1 protein (p.Pro824Ser). This variant is present in population databases (rs138188555, gnomAD 0.03%). This missense change has been observed in individual(s) with aplastic anemia (PMID: 29344583). This variant is also known as NM_032957.4, c.2542C>T (p.Pro848Ser). ClinVar contains an entry for this variant (Variation ID: 967062). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Tolerated"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0". The serine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. 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	RCV001836214	SCV002535324	uncertain significance	Dyskeratosis congenita	2022-02-23	criteria provided, single submitter	curation
Fulgent Genetics, Fulgent Genetics	RCV001241882	SCV002792854	uncertain significance	Dyskeratosis congenita, autosomal recessive 5; Pulmonary fibrosis and/or bone marrow failure, Telomere-related, 3	2021-07-27	criteria provided, single submitter	clinical testing
GeneDx	RCV001358128	SCV003805253	uncertain significance	not provided	2022-08-15	criteria provided, single submitter	clinical testing	In silico analysis supports that this missense variant does not alter protein structure/function; Identified in an individual with hematologic disease (Marsh et al., 2018); This variant is associated with the following publications: (PMID: 29344583)
Mayo Clinic Laboratories, Mayo Clinic	RCV001358128	SCV004225524	uncertain significance	not provided	2022-05-19	criteria provided, single submitter	clinical testing	BP4
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001358128	SCV001553783	uncertain significance	not provided		no assertion criteria provided	clinical testing	The RTEL1 p.Pro824Ser variant was not identified in the literature nor was it identified in ClinVar, Cosmic, or LOVD 3.0. The variant was identified in dbSNP (ID: rs138188555) and in control databases in 47 of 263374 chromosomes at a frequency of 0.000178 (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: European (non-Finnish) in 42 of 119276 chromosomes (freq: 0.000352), Other in 2 of 6768 chromosomes (freq: 0.000296), African in 2 of 22782 chromosomes (freq: 0.000088) and Latino in 1 of 33936 chromosomes (freq: 0.000029); the variant was not observed in the Ashkenazi Jewish, East Asian, European (Finnish), and South Asian populations. The p.Pro824 residue is not conserved in mammals and four out of five computational analyses (PolyPhen-2, SIFT, AlignGVGD, MutationTaster) do not suggest a high likelihood of impact to the protein; however, this information is not predictive enough to rule out pathogenicity. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) do not predict a difference in splicing. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of uncertain significance.
Natera, Inc.	RCV001836214	SCV002095463	uncertain significance	Dyskeratosis congenita	2020-01-15	no assertion criteria provided	clinical testing
Genetic Services Laboratory, University of Chicago	RCV003151295	SCV003839998	uncertain significance	not specified	2022-01-19	no assertion criteria provided	clinical testing	DNA sequence analysis of the RTEL1 gene demonstrated a sequence change, c.2542C>T, in exon 27 that results in an amino acid change, p.Pro848Ser (NM_032957.4). This sequence change has been described in the gnomAD database with a frequency of 0.035% in the non-Finnish European subpopulation (dbSNP rs138188555). The p.Pro848Ser change affects a poorly conserved amino acid residue located in a domain of the RTEL1 protein that is not known to be functional. The p.Pro848Ser substitution appears to be benign using several in-silico pathogenicity prediction tools (SIFT, Align GVGD, REVEL,Polyphen-2). This sequence change does not appear to have been previously described in individuals with RTEL1-related disorders. Due to insufficient evidences and the lack of functional studies, the clinical significance of the p.Pro848Ser change remains unknown at this time.