ClinVar Miner

Submissions for variant NM_020975.6(RET):c.1424G>A (p.Arg475Gln)

gnomAD frequency: 0.00002  dbSNP: rs138624658
Minimum review status: Collection method:
Minimum conflict level:
ClinVar version:
Total submissions: 7
Download table as spreadsheet
Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
CSER _CC_NCGL, University of Washington RCV000148779 SCV000190517 uncertain significance Aganglionic megacolon 2014-06-01 criteria provided, single submitter research Low GERP score may suggest that this variant may belong in a lower pathogenicity class
Labcorp Genetics (formerly Invitae), Labcorp RCV000470554 SCV000543838 uncertain significance Multiple endocrine neoplasia, type 2 2023-10-18 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 475 of the RET protein (p.Arg475Gln). This variant is present in population databases (rs138624658, gnomAD 0.007%). This missense change has been observed in individual(s) with Hirschsprung disease (PMID: 20473317). ClinVar contains an entry for this variant (Variation ID: 135188). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Not Available"; PolyPhen-2: "Benign"; Align-GVGD: "Not Available". The glutamine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. 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 RCV001011481 SCV001171807 uncertain significance Hereditary cancer-predisposing syndrome 2024-04-18 criteria provided, single submitter clinical testing The p.R475Q variant (also known as c.1424G>A), located in coding exon 7 of the RET gene, results from a G to A substitution at nucleotide position 1424. The arginine at codon 475 is replaced by glutamine, an amino acid with highly similar properties. This variant has been reported in a patient with sporadic Hirschsprung disease (Attié T et al. Hum. Mol. Genet. 1995 Aug;4:1381-6). This amino acid position is poorly 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.
All of Us Research Program, National Institutes of Health RCV000470554 SCV004821574 uncertain significance Multiple endocrine neoplasia, type 2 2023-09-05 criteria provided, single submitter clinical testing This missense variant replaces arginine with glutamine at codon 475 of the RET protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been observed in an individual with sporadic Hirschsprung disease (PMID: 20473317) and has also been identified in a healthy subject (PMID: 24728327) This variant has been identified in 3/251358 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.
Baylor Genetics RCV004567054 SCV005054196 uncertain significance Hirschsprung disease, susceptibility to, 1 2024-02-06 criteria provided, single submitter clinical testing
GeneDx RCV004589591 SCV005080194 uncertain significance not provided 2023-06-05 criteria provided, single submitter clinical testing Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant does not alter protein structure/function; Observed in individual(s) with Hirschsprung disease (Attie et al., 1995); This variant is associated with the following publications: (PMID: 24728327, 25637381, 8852653, 14633923, 7581377, 20473317, 30122538)
ITMI RCV000121995 SCV000086206 not provided not specified 2013-09-19 no assertion provided reference population

The information on this website is not intended for direct diagnostic use or medical decision-making without review by a genetics professional. Individuals should not change their health behavior solely on the basis of information contained on this website. Neither the University of Utah nor the National Institutes of Health independently verfies the submitted information. If you have questions about the information contained on this website, please see a health care professional.