ClinVar Miner

Submissions for variant NM_020975.6(RET):c.2973G>C (p.Glu991Asp)

gnomAD frequency: 0.00001  dbSNP: rs1351903863
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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Labcorp Genetics (formerly Invitae), Labcorp RCV000813839 SCV000954218 uncertain significance Multiple endocrine neoplasia, type 2 2022-06-15 criteria provided, single submitter clinical testing This variant is present in population databases (no rsID available, gnomAD 0.007%). This sequence change replaces glutamic acid, which is acidic and polar, with aspartic acid, which is acidic and polar, at codon 991 of the RET protein (p.Glu991Asp). 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: 657264). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C0"). 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 RCV002440777 SCV002751347 uncertain significance Hereditary cancer-predisposing syndrome 2024-08-31 criteria provided, single submitter clinical testing The p.E991D variant (also known as c.2973G>C), located in coding exon 18 of the RET gene, results from a G to C substitution at nucleotide position 2973. The glutamic acid at codon 991 is replaced by aspartic acid, an amino acid with highly similar properties. This amino acid position is highly 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 RCV000813839 SCV004838704 uncertain significance Multiple endocrine neoplasia, type 2 2023-11-30 criteria provided, single submitter clinical testing This missense variant replaces glutamic acid with aspartic acid at codon 991 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 not been reported in individuals affected with hereditary cancer in the literature. This variant has been identified in 1/251486 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.

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