ClinVar Miner

Submissions for variant NM_020975.6(RET):c.938G>A (p.Arg313Gln) (rs77702891)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000566081 SCV000674841 uncertain significance Hereditary cancer-predisposing syndrome 2019-03-13 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 variant has been previously reported in multiple individuals affected with Hirschsprung disease (Seri M et al. Hum. Mutat., 1997;9:243-9; So MT et al. PLoS ONE, 2011 Dec;6:e28986). Another alteration at the same codon (p.R313W) has also been detected in an individual with Hirschspring disease (Núñez-Torres R et al. BMC Med. Genet., 2011 Oct;12:138). However, it has not to date been reported in an individual meeting criteria for multiple endocrine neoplasia type 2 (MEN2). Based on protein sequence alignment, this amino acid position is well conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Invitae RCV000654592 SCV000776486 uncertain significance Multiple endocrine neoplasia, type 2 2018-12-07 criteria provided, single submitter clinical testing This sequence change replaces arginine with glutamine at codon 313 of the RET protein (p.Arg313Gln). The arginine residue is weakly conserved and there is a small physicochemical difference between arginine and glutamine. This variant is present in population databases (rs77702891, ExAC 0.1%) and has an allele count higher than expected for a pathogenic variant (PMID: 28166811). This variant has been reported in individuals affected with hirschsprung disease (PMID: 9090527, 22174939). ClinVar contains an entry for this variant (Variation ID: 13932). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. 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 RCV000764894 SCV000896054 uncertain significance Congenital central hypoventilation; Hirschsprung disease 1; Multiple endocrine neoplasia, type 2b; Pheochromocytoma; Familial medullary thyroid carcinoma; Multiple endocrine neoplasia, type 2a 2018-10-31 criteria provided, single submitter clinical testing
OMIM RCV000014957 SCV000035213 risk factor Hirschsprung disease 1 1997-01-01 no assertion criteria provided literature only

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