Submissions for variant NM_020975.6(RET):c.2488G>A (p.Gly830Arg)

gnomAD frequency: 0.00002  dbSNP: rs200127630

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Counsyl	RCV000409178	SCV000489755	uncertain significance	Multiple endocrine neoplasia type 2B	2015-12-01	criteria provided, single submitter	clinical testing
Counsyl	RCV000410477	SCV000489756	uncertain significance	Multiple endocrine neoplasia type 2A	2015-12-01	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV000704852	SCV000833823	uncertain significance	Multiple endocrine neoplasia, type 2	2023-12-04	criteria provided, single submitter	clinical testing	This sequence change replaces glycine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 830 of the RET protein (p.Gly830Arg). This variant is present in population databases (rs200127630, gnomAD 0.05%). This missense change has been observed in individual(s) with Hirschsprung disease (PMID: 22174939). ClinVar contains an entry for this variant (Variation ID: 372078). 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 arginine 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	RCV002429338	SCV002742233	benign	Hereditary cancer-predisposing syndrome	2022-04-19	criteria provided, single submitter	clinical testing	This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.
Fulgent Genetics, Fulgent Genetics	RCV002505998	SCV002814675	uncertain significance	Hirschsprung disease, susceptibility to, 1; Multiple endocrine neoplasia type 2B; Pheochromocytoma; Familial medullary thyroid carcinoma; Multiple endocrine neoplasia type 2A	2022-03-09	criteria provided, single submitter	clinical testing
Myriad Genetics, Inc.	RCV000410477	SCV004018056	likely benign	Multiple endocrine neoplasia type 2A	2024-08-13	criteria provided, single submitter	clinical testing	This variant is considered likely benign. This variant has been observed at a population frequency that is significantly greater than expected given the associated disease prevalence and penetrance.
PreventionGenetics, part of Exact Sciences	RCV004529566	SCV004106401	uncertain significance	RET-related disorder	2022-12-28	criteria provided, single submitter	clinical testing	The RET c.2488G>A variant is predicted to result in the amino acid substitution p.Gly830Arg. This variant was reported in an individual with Hirschsprung disease (Table S4, So et al. 2011. PubMed ID: 22174939), however in another study, this variant was only detected in the control group (Supplementary Table 4, Tang et al. 2018. PubMed ID: 30217742). This variant is reported in 0.071% of alleles in individuals of East Asian descent in gnomAD (http://gnomad.broadinstitute.org/variant/10-43615074-G-A). In ClinVar, this variant has conflicting interpretations, ranging from benign to uncertain (https://www.ncbi.nlm.nih.gov/clinvar/variation/372078). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.