ClinVar Miner

Submissions for variant NM_020975.6(RET):c.2081G>A (p.Arg694Gln) (rs141185224)

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Total submissions: 8
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Counsyl RCV000411751 SCV000489777 uncertain significance Multiple endocrine neoplasia, type 2b 2015-12-29 criteria provided, single submitter clinical testing
Counsyl RCV000409290 SCV000489778 uncertain significance Multiple endocrine neoplasia, type 2a 2015-12-29 criteria provided, single submitter clinical testing
Laboratory for Molecular Medicine, Partners HealthCare Personalized Medicine RCV000455880 SCV000540170 uncertain significance not specified 2016-04-25 criteria provided, single submitter clinical testing Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: Found in 1 HSCR proband; ExAC: 8/16314 South Asian chromosomes
Invitae RCV000462012 SCV000543797 uncertain significance Multiple endocrine neoplasia, type 2 2018-12-24 criteria provided, single submitter clinical testing This sequence change replaces arginine with glutamine at codon 694 of the RET protein (p.Arg694Gln). The arginine residue is highly conserved and there is a small physicochemical difference between arginine and glutamine. This variant is present in population databases (rs141185224, ExAC 0.05%). This variant has been reported in an individual affected with sporadic Hirschsprung disease, however, it was also identified in this individual's unaffected father (PMID: 14633923). In addition, this variant has been reported in a proband with autoimmune thyroiditis and premature ovarian failure, but with no history or clinical/biochemical evidence of familial medullary thyroid cancer, multiple endocrine neoplasia 2A or 2B, or Hirschsprung disease in the proband or any first degree relatives (PMID: 15472167). In this family, the proband's mother, who was affected with autoimmune thyroiditis, also carried this variant, while the proband's sister, who was affected with autoimmune thyroiditis and premature ovarian failure, did not carry this variant. ClinVar contains an entry for this variant (Variation ID: 161358). Experimental studies have shown that this missense change does not demonstrate any potentiating effects on RET kinase activity or transforming ability (PMID: 15472167). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may alter RNA splicing, but this prediction has not been confirmed by published transcriptional studies. 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.
GeneDx RCV000766923 SCV000583217 uncertain significance not provided 2017-05-25 criteria provided, single submitter clinical testing The R694Q variant in the RET gene has been observed in cases of Hirschprung disease (Garcia-Barcelo et al., 2004; So et al., 2011; Widowati 2015). Functional studies demonstrated this variant results in lack of in vitro transforming activity, and phosphorylation of the variant RET protein was not significantly different compared to wild type (Orgiana et al., 2004; Widowati et al., 2015). The R694Q variant was observed at an allele frequency of 0.049% (8/16314) in individuals of South Asian ancestry in large population cohorts (NHLBI Exome Sequencing Project, The 1000 Genomes Consortium 2015, Lek et al, 2016). Since Arginine and Glutamine differ in some properties, this is considered a semi-conservative amino acid substitution. This substitution occurs at a position that is not conserved and is located in the intracellular domain (Garcia-Barcelo et al., 2004). Based on currently available evidence, we consider R694Q to be a variant of uncertain significance.
Ambry Genetics RCV000562835 SCV000674746 likely benign Hereditary cancer-predisposing syndrome 2019-02-27 criteria provided, single submitter clinical testing In silico models in agreement (benign);Other data supporting benign classification
Mendelics RCV000409290 SCV000838394 uncertain significance Multiple endocrine neoplasia, type 2a 2018-07-02 criteria provided, single submitter clinical testing
CSER _CC_NCGL, University of Washington RCV000148781 SCV000190519 uncertain significance Hirschsprung disease 2014-06-01 no assertion criteria provided research

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