Submissions for variant NM_020975.6(RET):c.334C>T (p.Arg112Cys)

gnomAD frequency: 0.00001  dbSNP: rs762626209

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV000200291	SCV000255055	uncertain significance	Multiple endocrine neoplasia, type 2	2024-01-09	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 112 of the RET protein (p.Arg112Cys). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This variant has not been reported in the literature in individuals affected with RET-related conditions. ClinVar contains an entry for this variant (Variation ID: 216726). 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. 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.
Illumina Laboratory Services, Illumina	RCV000380664	SCV000362234	uncertain significance	Renal hypodysplasia/aplasia 1	2018-01-12	criteria provided, single submitter	clinical testing	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease.
Illumina Laboratory Services, Illumina	RCV000283887	SCV000362235	uncertain significance	Multiple endocrine neoplasia	2018-01-12	criteria provided, single submitter	clinical testing	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease.
Illumina Laboratory Services, Illumina	RCV000322527	SCV000362236	uncertain significance	Pheochromocytoma	2018-01-12	criteria provided, single submitter	clinical testing	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease.
Illumina Laboratory Services, Illumina	RCV000374792	SCV000362237	uncertain significance	Hirschsprung disease, susceptibility to, 1	2018-01-12	criteria provided, single submitter	clinical testing	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease.
Ambry Genetics	RCV000572326	SCV000674776	uncertain significance	Hereditary cancer-predisposing syndrome	2023-03-17	criteria provided, single submitter	clinical testing	The p.R112C variant (also known as c.334C>T), located in coding exon 2 of the RET gene, results from a C to T substitution at nucleotide position 334. The arginine at codon 112 is replaced by cysteine, an amino acid with highly dissimilar properties. Based on data from gnomAD, the frequency for this variant is above the maximum credible frequency for a disease-causing variant associated with Multiple Endocrine Neoplasia, Type 2 (MEN2) in this gene 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). This amino acid position is well conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. 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	RCV000663300	SCV000786553	uncertain significance	Multiple endocrine neoplasia, type 2a	2018-05-22	criteria provided, single submitter	clinical testing
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	RCV002470810	SCV002769270	uncertain significance	Congenital anomaly of kidney and urinary tract	2020-05-21	criteria provided, single submitter	clinical testing	Based on the classification scheme VCGS_Germline_v1.1.1, this variant is classified as VOUS. Following criteria are met: 0103 - Both loss- and gain-of-function are known mechanisms of disease for this gene. (N) 0107 - This gene is known to be associated with autosomal dominant disease. (N) 0112 - Variants in this gene are known to have reduced penetrance (OMIM). (N) 0200 - Variant is predicted to result in a missense amino acid change from arginine to cysteine (exon 2). (N) 0251 - Variant is heterozygous. (N) 0302 - Variant is present in gnomAD <0.001 for a dominant condition (3 heterozygotes, 0 homozygote). (P) 0309 - An alternative amino acid change at the same position has been observed in gnomAD (6 heterozygotes, 0 homozygote). (N) 0502 - Missense variant with conflicting in-silico predictions and/or uninformative conservation (PolyPhen2, PROVEAN, MutationAssessor, FATHMM, UCSC). (N) 0600 - Variant is located in an annotated domain or motif (RET Cadherin like domain 1; PDB). (N) 0705 - No comparable variants have previous evidence for pathogenicity. (N) 0804 - Variant has previously been described as variant of uncertain significance in multiple independent cases (ClinVar). (N) 0905 - No segregation evidence has been identified for this variant. (N) 1007 - No published functional evidence has been identified for this variant. (N) Legend: (P) - Pathogenic, (N) - Neutral, (B) - Benign
Baylor Genetics	RCV000374792	SCV004206732	uncertain significance	Hirschsprung disease, susceptibility to, 1	2023-05-22	criteria provided, single submitter	clinical testing