Submissions for variant NM_020975.6(RET):c.1888T>C (p.Cys630Arg)

dbSNP: rs377767404

Total submissions: 3

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000654593	SCV000776487	pathogenic	Multiple endocrine neoplasia, type 2	2023-12-13	criteria provided, single submitter	clinical testing	This sequence change replaces cysteine, which is neutral and slightly polar, with arginine, which is basic and polar, at codon 630 of the RET protein (p.Cys630Arg). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with medullary thyroid carcinoma (MTC) (PMID: 14561794, 15523405, 16053382, 25440022). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 24908). 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 disruptive. Experimental studies have shown that this missense change affects RET function (PMID: 9879991). This variant disrupts the p.Cys630 amino acid residue in RET. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 9223675, 17527003, 21054478, 26678667). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000654593	SCV002041764	pathogenic	Multiple endocrine neoplasia, type 2	2021-11-01	criteria provided, single submitter	clinical testing	Variant summary: RET c.1888T>C (p.Cys630Arg) results in a non-conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 246688 control chromosomes. c.1888T>C has been reported in the literature in multiple individuals affected with Multiple Endocrine Neoplasia Type 2/Familial Medullary Thyroid Carcinoma (example, Machens_2004, Dourisboure_2005). These data indicate that the variant is very likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function (example, Chappuis-Flament_1998). The most pronounced variant effect results in the constitutive activation of the RET receptor consistent with the established gain of function mechanism of disease. Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Ambry Genetics	RCV004943733	SCV005490935	pathogenic	Hereditary cancer-predisposing syndrome	2024-07-06	criteria provided, single submitter	clinical testing	The p.C630R variant (also known as c.1888T>C), located in coding exon 11 of the RET gene, results from a T to C substitution at nucleotide position 1888. The cysteine at codon 630 is replaced by arginine, an amino acid with highly dissimilar properties. This variant has been seen in multiple individuals and families diagnosed with medullary thyroid carcinoma (MTC), as well as in an individual with both an MTC and a parathyroid adenoma (Machens A et al. Surgery, 2004 Nov;136:1083-7; Elisei R et al. J. Clin. Endocrinol. Metab., 2007 Dec;92:4725-9; Romei C et al. Eur J Endocrinol, 2010 Aug;163:301-8; Martins-Costa MC et al. Arch Endocrinol Metab, 2018;62:623-635; Damavandi E et al. J Thyroid Res, 2021 Nov;2021:7250870). Additionally, it was shown to segregate with disease in a large kindred of more than 20 family members (Dourisboure RJ et al. Thyroid, 2005 Jul;15:668-71). This alteration was also shown to be an activating mutation which leads to a constitutive stimulation of the RET receptor by functional analysis (Chappuis-Flament S et al. Oncogene, 1998 Dec;17:2851-61). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). Based on the supporting evidence, this alteration is pathogenic for MEN2; however, the association of this alteration with Hirschsprung disease is unknown.