ClinVar Miner

Submissions for variant NM_020975.6(RET):c.431G>A (p.Arg144His)

gnomAD frequency: 0.00001  dbSNP: rs551142665
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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000200522 SCV000255058 uncertain significance Multiple endocrine neoplasia, type 2 2023-12-27 criteria provided, single submitter clinical testing This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 144 of the RET protein (p.Arg144His). This variant is present in population databases (rs551142665, gnomAD 0.02%). This missense change has been observed in individual(s) with Hirschsprung disease (PMID: 26395553). ClinVar contains an entry for this variant (Variation ID: 216729). 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.
Ambry Genetics RCV000565710 SCV000674838 uncertain significance Hereditary cancer-predisposing syndrome 2022-10-04 criteria provided, single submitter clinical testing The p.R144H variant (also known as c.431G>A), located in coding exon 3 of the RET gene, results from a G to A substitution at nucleotide position 431. The arginine at codon 144 is replaced by histidine, an amino acid with highly similar properties. This alteration has been reported in one individual from a cohort of 61 children with Hirschsprung disease (Widowati T et al. Eur J Hum Genet, 2016 Jun;24:823-9). This amino acid position is not well conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Based on data from gnomAD, the frequency for this variant is above the maximum credible frequency for a disease-causing variant in association with MEN2 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.
Counsyl RCV000662542 SCV000785121 uncertain significance Multiple endocrine neoplasia, type 2a 2017-05-03 criteria provided, single submitter clinical testing
Baylor Genetics RCV001294032 SCV001482797 uncertain significance Familial medullary thyroid carcinoma 2020-05-21 criteria provided, single submitter clinical testing This variant was determined to be of uncertain significance according to ACMG Guidelines, 2015 [PMID:25741868].
Fulgent Genetics, Fulgent Genetics RCV002500624 SCV002789141 uncertain significance Hirschsprung disease, susceptibility to, 1; Multiple endocrine neoplasia, type 2b; Pheochromocytoma; Familial medullary thyroid carcinoma; Multiple endocrine neoplasia, type 2a 2021-11-10 criteria provided, single submitter clinical testing

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