ClinVar Miner

Submissions for variant NM_020975.6(RET):c.3314C>T (p.Ala1105Val) (rs532862288)

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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Laboratory for Molecular Medicine, Partners HealthCare Personalized Medicine RCV000456051 SCV000540179 uncertain significance not specified 2016-10-27 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: This variant is classidied as DM? in HGMD, related to urinary tract malformation. It is classified in ClinVar with 1 star as likely path by GeneDx, though their evidence provided does not support this classification. The Max MAF in ExAC is 0.02% (2/11578 Latino chrs).
Invitae RCV000463602 SCV000543794 uncertain significance Multiple endocrine neoplasia, type 2 2020-10-15 criteria provided, single submitter clinical testing This sequence change replaces alanine with valine at codon 1105 of the RET protein (p.Ala1105Val). The alanine residue is moderately conserved and there is a small physicochemical difference between alanine and valine. This variant is present in population databases (rs532862288, ExAC 0.02%). This variant has been reported in an individual affected with congenital anomalies of the kidney or urinary tract (PMID: 22729463). ClinVar contains an entry for this variant (Variation ID: 201136). Experimental studies have shown that this missense change does not significantly affect the induction of MAPK activity when compared to wild-type RET (PMID: 22729463). 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.
Counsyl RCV000662469 SCV000784959 uncertain significance Multiple endocrine neoplasia, type 2a 2017-02-22 criteria provided, single submitter clinical testing
Mendelics RCV000662469 SCV000838411 uncertain significance Multiple endocrine neoplasia, type 2a 2018-07-02 criteria provided, single submitter clinical testing
Fulgent Genetics,Fulgent Genetics RCV000763652 SCV000894532 uncertain significance Congenital central hypoventilation; Hirschsprung disease 1; Multiple endocrine neoplasia, type 2b; Pheochromocytoma; Familial medullary thyroid carcinoma; Multiple endocrine neoplasia, type 2a 2018-10-31 criteria provided, single submitter clinical testing
Ambry Genetics RCV001019923 SCV001181339 uncertain significance Hereditary cancer-predisposing syndrome 2020-10-09 criteria provided, single submitter clinical testing The p.A1105V variant (also known as c.3314C>T), located in coding exon 20 of the RET gene, results from a C to T substitution at nucleotide position 3314. The alanine at codon 1105 is replaced by valine, an amino acid with similar properties. This alteration was reported in an individual with multicystic renal dysplasia; however, functional studies indicated that this alteration did not significantly alter GDNF-dependent MAPK activity compared to wild-type RET, indicating that this alteration may not be causative (Chatterjee R et al. Hum. Genet. 2012 Nov;131(11):1725-38). This amino acid position is highly conserved through mammals but not in all 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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