ClinVar Miner

Submissions for variant NM_020975.6(RET):c.1008C>G (p.Asn336Lys)

gnomAD frequency: 0.00001  dbSNP: rs144981275
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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Labcorp Genetics (formerly Invitae), Labcorp RCV000814407 SCV000954816 uncertain significance Multiple endocrine neoplasia, type 2 2024-01-02 criteria provided, single submitter clinical testing This sequence change replaces asparagine, which is neutral and polar, with lysine, which is basic and polar, at codon 336 of the RET protein (p.Asn336Lys). This variant is present in population databases (rs144981275, gnomAD 0.007%). 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: 657732). 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 RCV001009678 SCV001169776 uncertain significance Hereditary cancer-predisposing syndrome 2023-06-18 criteria provided, single submitter clinical testing The p.N336K variant (also known as c.1008C>G), located in coding exon 5 of the RET gene, results from a C to G substitution at nucleotide position 1008. The asparagine at codon 336 is replaced by lysine, an amino acid with similar properties. This amino acid position is well conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Baylor Genetics RCV003467473 SCV004208725 uncertain significance Hirschsprung disease, susceptibility to, 1 2023-07-19 criteria provided, single submitter clinical testing
Myriad Genetics, Inc. RCV004792517 SCV005403629 likely benign Multiple endocrine neoplasia type 2A 2024-08-07 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 RCV004740458 SCV005349022 uncertain significance RET-related disorder 2024-07-30 no assertion criteria provided clinical testing The RET c.1008C>G variant is predicted to result in the amino acid substitution p.Asn336Lys. To our knowledge, this variant has not been reported in the literature. This variant is reported in 0.012% of alleles in individuals of African descent in gnomAD, and it has been classified as a variant of uncertain significance in ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/variation/657732/). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.

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