ClinVar Miner

Submissions for variant NM_020975.6(RET):c.235C>T (p.Arg79Trp) (rs537523906)

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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000463969 SCV000543820 uncertain significance Multiple endocrine neoplasia, type 2 2020-10-25 criteria provided, single submitter clinical testing This sequence change replaces arginine with tryptophan at codon 79 of the RET protein (p.Arg79Trp). The arginine residue is moderately conserved and there is a moderate physicochemical difference between arginine and tryptophan. This variant is present in population databases (rs537523906, ExAC 0.05%). This variant has been reported in an individual with Hirschsprung disease (PMID: 26395553). ClinVar contains an entry for this variant (Variation ID: 405541). An experimental study has shown that this missense change does not affect phosphorylation of the RET and ERK proteins compared to the wild-type RET protein (PMID: 26395553). 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 RCV001015286 SCV001176103 uncertain significance Hereditary cancer-predisposing syndrome 2020-09-24 criteria provided, single submitter clinical testing The p.R79W variant (also known as c.235C>T), located in coding exon 2 of the RET gene, results from a C to T substitution at nucleotide position 235. The arginine at codon 79 is replaced by tryptophan, an amino acid with dissimilar properties. This alteration has been reported in an individual with Hirschsprung disease; however, p.R79W showed comparable performance to the wildtype control in a functional assay (Widowati T et al. Eur. J. Hum. Genet. 2016 Jun;24:823-9). This amino acid position is well conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Illumina Clinical Services Laboratory,Illumina RCV001104288 SCV001261140 benign Pheochromocytoma 2017-04-27 criteria provided, single submitter clinical testing This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases was too high to be consistent with this variant causing disease. Therefore, this variant is classified as benign.
Illumina Clinical Services Laboratory,Illumina RCV001105645 SCV001262630 uncertain significance Renal hypodysplasia/aplasia 1 2017-04-27 criteria provided, single submitter clinical testing This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.
Illumina Clinical Services Laboratory,Illumina RCV001105646 SCV001262631 benign Multiple endocrine neoplasia 2017-04-27 criteria provided, single submitter clinical testing This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases was too high to be consistent with this variant causing disease. Therefore, this variant is classified as benign.
Illumina Clinical Services Laboratory,Illumina RCV001105647 SCV001262632 uncertain significance Hirschsprung disease 1 2017-04-27 criteria provided, single submitter clinical testing This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.

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