Submissions for variant NM_020975.6(RET):c.938G>A (p.Arg313Gln)

gnomAD frequency: 0.00002  dbSNP: rs77702891

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000566081	SCV000674841	uncertain significance	Hereditary cancer-predisposing syndrome	2023-12-29	criteria provided, single submitter	clinical testing	The p.R313Q variant (also known as c.938G>A), located in coding exon 5 of the RET gene, results from a G to A substitution at nucleotide position 938. The arginine at codon 313 is replaced by glutamine, an amino acid with highly similar properties. This alteration has been reported in a homozygous state in a child born to consanguineous parents with the most severe Hirschsprung disease phenotype (total colonic aganglionosis with small bowel involvement) (Seri M et al. Hum. Mutat. 1997;9:243-9). This alteration has also been reported in a cohort of 601 Chinese Hirschsprung disease patients (So MT et al. PLoS One. 2011 Dec;6:e28986). This amino acid position is well conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Based on data from gnomAD, the frequency for this variant is above the maximum credible frequency for a multiple endocrine neoplasia type 2 (MEN2) disease-causing variant in this gene based on internally established thresholds (Karczewski et al. Nature. 2020 May;581(7809):434-443; Whiffin et al. Genet Med. 2017 10;19:1151-1158). Based on the supporting evidence, the association of this alteration with Hirschsprung disease is unknown; however, the association of this alteration with MEN2 is unlikely.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000654592	SCV000776486	uncertain significance	Multiple endocrine neoplasia, type 2	2025-01-24	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 313 of the RET protein (p.Arg313Gln). This variant is present in population databases (rs77702891, gnomAD 0.08%), and has an allele count higher than expected for a pathogenic variant. This missense change has been observed in individual(s) with Hirschsprung disease (PMID: 9090527, 22174939, 29315604). ClinVar contains an entry for this variant (Variation ID: 13932). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be tolerated. 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.
Counsyl	RCV000662693	SCV000785424	uncertain significance	Multiple endocrine neoplasia type 2A	2017-07-27	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV002476968	SCV000896054	uncertain significance	Hirschsprung disease, susceptibility to, 1; Multiple endocrine neoplasia type 2B; Pheochromocytoma; Familial medullary thyroid carcinoma; Multiple endocrine neoplasia type 2A	2024-03-19	criteria provided, single submitter	clinical testing
GeneDx	RCV003114192	SCV003798648	uncertain significance	not provided	2022-10-28	criteria provided, single submitter	clinical testing	Also reported in a patient with short segment Hirschsprung disease, but it is unknown whether this individual was screened for variants in other genes associated with this phenotype (So et al., 2011); In silico analysis supports that this missense variant does not alter protein structure/function; Reported in the homozygous state in a patient with total colonic aganglionosis with small bowel involvement who underwent targeted testing of the RET gene; both parents of this individual were heterozygous for this variant and were reportedly healthy (Seri et al., 1997); This variant is associated with the following publications: (PMID: 21995290, 9090527, 22174939)
Myriad Genetics, Inc.	RCV000662693	SCV004018491	uncertain significance	Multiple endocrine neoplasia type 2A	2023-04-18	criteria provided, single submitter	clinical testing	This variant is classified as a variant of uncertain significance as there is insufficient evidence to determine its impact on protein function and/or cancer risk.
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV003114192	SCV005623124	uncertain significance	not provided	2024-12-03	criteria provided, single submitter	clinical testing	The RET c.938G>A (p.Arg313Gln) variant has been reported in the published literature in individuals affected with pheochromocytoma (PMID: 29315604 (2018)) and biliary tract cancer (PMID: 35958441 (2022)). In addition, it was identified in individuals affected with Hirschsprung disease (PMID: 22174939 (2011), 23441071 (2013)) and in a homozygous child with a severe phenotype (PMID: 9090527 (1997)). A related variant affecting the same codon, c.937C>T (p.Arg313Trp), has also been reported in an individual with Hirschsprung disease (PMID: 21995290 (2011)). The frequency of the c.938G>A variant in the general population, 0.00076 (26/34410 chromosomes in Admixed American subpopulation (Genome Aggregation Database, http://gnomad.broadinstitute.org)), is higher than would generally be expected for pathogenic variants in this gene. Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded conflicting predictions that this variant is deleterious or benign. Based on the available information, we are unable to determine the clinical significance of this variant.
OMIM	RCV000014957	SCV000035213	risk factor	Hirschsprung disease, susceptibility to, 1	1997-01-01	no assertion criteria provided	literature only