ClinVar Miner

Submissions for variant NM_020975.6(RET):c.1876C>A (p.Gln626Lys)

dbSNP: rs1255575160
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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Counsyl RCV000663335 SCV000786612 uncertain significance Multiple endocrine neoplasia type 2A 2018-06-07 criteria provided, single submitter clinical testing
Mendelics RCV000663335 SCV000838390 uncertain significance Multiple endocrine neoplasia type 2A 2018-07-02 criteria provided, single submitter clinical testing
Labcorp Genetics (formerly Invitae), Labcorp RCV001035381 SCV001198706 uncertain significance Multiple endocrine neoplasia, type 2 2021-11-26 criteria provided, single submitter clinical testing This sequence change replaces glutamine, which is neutral and polar, with lysine, which is basic and polar, at codon 626 of the RET protein (p.Gln626Lys). This variant is present in population databases (no rsID available, gnomAD 0.0009%). This missense change has been observed in individual(s) with Hirschsprung disease (PMID: 10090908). ClinVar contains an entry for this variant (Variation ID: 548925). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Tolerated"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0". The lysine 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 RCV002406502 SCV002717843 uncertain significance Hereditary cancer-predisposing syndrome 2022-02-28 criteria provided, single submitter clinical testing The p.Q626K variant (also known as c.1876C>A), located in coding exon 10 of the RET gene, results from a C to A substitution at nucleotide position 1876. The glutamine at codon 626 is replaced by lysine, an amino acid with similar properties. This alteration has been detected in an individual with sporadic Hirschsprung disease (Auricchio A et al. Am J Hum Genet 1999 Apr;64(4):1216-21). This amino acid position is well 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.

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