ClinVar Miner

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

gnomAD frequency: 0.00001  dbSNP: rs532862288
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Total submissions: 8
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Laboratory for Molecular Medicine, Mass General Brigham 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 2023-12-30 criteria provided, single submitter clinical testing This sequence change replaces alanine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 1105 of the RET protein (p.Ala1105Val). This variant is present in population databases (rs532862288, gnomAD 0.006%). This missense change has been observed in individual(s) with congenital anomalies of the kidney or urinary tract and/or medullary thyroid cancer (PMID: 22729463, 33827484). ClinVar contains an entry for this variant (Variation ID: 201136). 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 disruptive. Experimental studies have shown that this missense change does not substantially affect RET function (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 RCV002478618 SCV000894532 uncertain significance Hirschsprung disease, susceptibility to, 1; Multiple endocrine neoplasia, type 2b; Pheochromocytoma; Familial medullary thyroid carcinoma; Multiple endocrine neoplasia, type 2a 2022-01-05 criteria provided, single submitter clinical testing
Ambry Genetics RCV001019923 SCV001181339 likely benign Hereditary cancer-predisposing syndrome 2023-01-18 criteria provided, single submitter clinical testing This alteration is classified as likely benign based on a combination of the following: population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.
Genetic Services Laboratory, University of Chicago RCV000456051 SCV002065782 uncertain significance not specified 2021-12-01 criteria provided, single submitter clinical testing DNA sequence analysis of the RET gene demonstrated a sequence change, c.3314C>T, in exon 20 that results in an amino acid change, p.Ala1105Val. This sequence change has been described in the gnomAD database with a frequency of 0.006% in the Latino/admixed American subpopulation (dbSNP rs532862288). The p.Ala1105Val change affects a poorly conserved amino acid residue located in a domain of the RET protein that is known to be functional. In-silico pathogenicity prediction tools (SIFT, PolyPhen2, Align GVGD, REVEL) provide contradictory results for the p.Ala1105Val substitution. This sequence change does not appear to have been previously described in individuals with RET-related disorders. Due to insufficient evidences and the lack of functional studies, the clinical significance of the p.Ala1105Val change remains unknown at this time.
Baylor Genetics RCV003462290 SCV004206714 uncertain significance Hirschsprung disease, susceptibility to, 1 2023-06-22 criteria provided, single submitter clinical testing

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