Submissions for variant NM_001283009.2(RTEL1):c.3178G>A (p.Val1060Met)

gnomAD frequency: 0.00005  dbSNP: rs116768542

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000807911	SCV000947991	uncertain significance	Dyskeratosis congenita, autosomal recessive 5; Pulmonary fibrosis and/or bone marrow failure, Telomere-related, 3	2022-09-06	criteria provided, single submitter	clinical testing	This sequence change replaces valine, which is neutral and non-polar, with methionine, which is neutral and non-polar, at codon 1060 of the RTEL1 protein (p.Val1060Met). This variant is present in population databases (rs116768542, gnomAD 0.07%). This variant has not been reported in the literature in individuals affected with RTEL1-related conditions. This variant is also known as c.3250G>A (p.Val1083Met) on transcript NM_032957.4. ClinVar contains an entry for this variant (Variation ID: 652372). 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: "Possibly 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.
Sema4, Sema4	RCV001273634	SCV002533583	uncertain significance	Dyskeratosis congenita	2022-03-08	criteria provided, single submitter	curation
Mayo Clinic Laboratories, Mayo Clinic	RCV001354808	SCV004225528	uncertain significance	not provided	2022-09-30	criteria provided, single submitter	clinical testing	BP4
GeneDx	RCV001354808	SCV005078031	uncertain significance	not provided	2023-10-03	criteria provided, single submitter	clinical testing	In silico analysis supports that this missense variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge
Natera, Inc.	RCV001273634	SCV001456925	uncertain significance	Dyskeratosis congenita	2020-09-16	no assertion criteria provided	clinical testing
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001354808	SCV001549513	uncertain significance	not provided		no assertion criteria provided	clinical testing	The RTEL1 p.Val1060Met variant was not identified in the literature but was identified in dbSNP (ID: rs116768542) and ClinVar (classified as uncertain significance by Invitae). The variant was identified in control databases in 21 of 279692 chromosomes at a frequency of 0.00007508 (Genome Aggregation Database March 6, 2019, v2.1.1). The variant was observed in the following populations: East Asian in 15 of 19852 chromosomes (freq: 0.000756), Latino in 2 of 35342 chromosomes (freq: 0.000057) and European (non-Finnish) in 4 of 126924 chromosomes (freq: 0.000032), but was not observed in the African, Ashkenazi Jewish, European (Finnish), Other, or South Asian populations. The p.Val1060 residue is not conserved in mammals and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, 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 3 of 4 in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) predict a greater than 10% difference in splicing. However, this has not been confirmed by RNA analysis and is not predictive enough to assume pathogenicity. 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.