Submissions for variant NM_001283009.2(RTEL1):c.3730T>C (p.Cys1244Arg)

gnomAD frequency: 0.00002  dbSNP: rs587777037

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Counsyl	RCV000055634	SCV000800482	uncertain significance	Dyskeratosis congenita, autosomal recessive 5	2017-04-28	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV002513726	SCV003518899	uncertain significance	Dyskeratosis congenita, autosomal recessive 5; Pulmonary fibrosis and/or bone marrow failure, Telomere-related, 3	2019-09-06	criteria provided, single submitter	clinical testing	This sequence change replaces cysteine with arginine at codon 1244 of the RTEL1 protein (p.Cys1244Arg). The cysteine residue is weakly conserved and there is a large physicochemical difference between cysteine and arginine. This variant is present in population databases (rs587777037, ExAC 0.003%). This variant has been observed to segregate with Hoyeraal–Hreidarsson syndrome in a family (PMID: 23591994). This variant has also been observed in an individual with aplastic anemia (PMID: 30995915). ClinVar contains an entry for this variant (Variation ID: 65412). 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.
Ambry Genetics	RCV003258663	SCV003945155	uncertain significance	Inborn genetic diseases	2023-05-22	criteria provided, single submitter	clinical testing	The c.3724+78T>C intronic alteration results from a T to C substitution 78 nucleotides after coding exon 33 of the RTEL1 gene._x000D_ _x000D_ _x000D_ _x000D_ The c.3730T>C (p.C1244R) alteration is located in exon 34 (coding exon 33) of the RTEL1 gene. This alteration results from a T to C substitution at nucleotide position 3730, causing the cysteine (C) at amino acid position 1244 to be replaced by an arginine (R). Based on data from gnomAD, the C allele has an overall frequency of 0.002% (5/247318) total alleles studied. The highest observed frequency was 0.005% (1/18282) of East Asian alleles. This variant was detected in two affected siblings with shortened telomere length and abnormal telomere function. Both of these siblings were compound heterozygous carriers of this variant as well as RTEL1 c.2097C>G (p.I699M) (Le Guen, 2013). This variant has also been detected in heterozygous form in a 61 year old female with idiopathic pulmonary fibrosis post lung transplant who also had severely shortened telomeres (Popescu, 2019). This nucleotide position is highly conserved in available vertebrate species._x000D_ _x000D_ Leave out nucleotide conservation sentence and table? The in silico prediction for this alteration is inconclusive. Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear.
GeneDx	RCV002464103	SCV005324886	likely pathogenic	not provided	2023-05-04	criteria provided, single submitter	clinical testing	In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Not observed at significant frequency in large population cohorts (gnomAD); Reported using an alternate transcript of the gene; Also known as c.3724+78T>C; This variant is associated with the following publications: (PMID: 23591994, 31130284, 30995915, 33718801)
OMIM	RCV000055634	SCV000083857	pathogenic	Dyskeratosis congenita, autosomal recessive 5	2013-08-15	no assertion criteria provided	literature only
Genetic Services Laboratory, University of Chicago	RCV002464103	SCV002072154	uncertain significance	not provided	2017-09-01	no assertion criteria provided	clinical testing	DNA sequence analysis of the RTEL1 gene demonstrated a sequence change, c.3730T>C, in exon 34 that results in an amino acid change, p.Cys1244Arg. The p.Cys1244Arg change affects a moderately conserved amino acid residue located in a domain of the RTEL1 protein that is known to be functional. The p.Cys1244Arg substitution appears to be deleterious using several in-silico pathogenicity prediction tools (SIFT, PolyPhen2, REVEL). This variant is present in 5 individuals in gnomAD (0.002% frequency in the global population). This sequence change has been described in the compound heterozygous state with another variant in two siblings with Hoyeraal-Hreidarsson syndrome and not present in their unaffected sibling (Le Guen et al. 2013). Additionally, analysis of these patient's primary fibroblasts demonstrated shorter telomeres and genome instability (Le Guen et al. 2013).