ClinVar Miner

Submissions for variant NM_020975.6(RET):c.134C>T (p.Ala45Val)

gnomAD frequency: 0.00002  dbSNP: rs763526874
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Total submissions: 10
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000489446 SCV000577198 uncertain significance not provided 2020-08-28 criteria provided, single submitter clinical testing In silico analysis supports that this missense variant does not alter protein structure/function; Has not been previously published as a pathogenic or benign germline variant to our knowledge; This variant is associated with the following publications: (PMID: 28350084)
Ambry Genetics RCV000568194 SCV000664523 uncertain significance Hereditary cancer-predisposing syndrome 2021-07-16 criteria provided, single submitter clinical testing The p.A45V variant (also known as c.134C>T), located in coding exon 2 of the RET gene, results from a C to T substitution at nucleotide position 134. The alanine at codon 45 is replaced by valine, an amino acid with similar properties. This amino acid position is poorly 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.
Counsyl RCV000662783 SCV000785592 uncertain significance Multiple endocrine neoplasia type 2A 2017-09-26 criteria provided, single submitter clinical testing
GeneKor MSA RCV000568194 SCV000822189 uncertain significance Hereditary cancer-predisposing syndrome 2018-08-01 criteria provided, single submitter clinical testing
Mendelics RCV000662783 SCV000838365 uncertain significance Multiple endocrine neoplasia type 2A 2018-07-02 criteria provided, single submitter clinical testing
Genetic Services Laboratory, University of Chicago RCV001821237 SCV002068662 uncertain significance not specified 2019-03-04 criteria provided, single submitter clinical testing
Fulgent Genetics, Fulgent Genetics RCV002481388 SCV002776426 uncertain significance Hirschsprung disease, susceptibility to, 1; Multiple endocrine neoplasia type 2B; Pheochromocytoma; Familial medullary thyroid carcinoma; Multiple endocrine neoplasia type 2A 2021-11-06 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV001821237 SCV003801162 uncertain significance not specified 2023-01-16 criteria provided, single submitter clinical testing Variant summary: RET c.134_135delinsTG (p.Ala45Val) results in a non-conservative amino acid change located in the RET Cadherin like domain 1 (IPR041163) of the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 2.4e-05 in 249804 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.134_135delinsTG has been reported in the literature in an individual referred for genetic testing with a hereditary cancer panel (Tsaousis_2019). This report does not provide unequivocal conclusions about association of the variant with Multiple Endocrine Neoplasia Type 2. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014. However, a different variant resulting in the same amino acid change (c.134C>T, p.Ala45Val) has been cited in ClinVar as a variant of uncertain significance by eight submitters (evaluation after 2014). Based on the evidence outlined above, the variant was classified as uncertain significance.
Baylor Genetics RCV003463861 SCV004208697 uncertain significance Hirschsprung disease, susceptibility to, 1 2024-03-21 criteria provided, single submitter clinical testing
All of Us Research Program, National Institutes of Health RCV004000673 SCV004838624 uncertain significance Multiple endocrine neoplasia, type 2 2024-02-05 criteria provided, single submitter clinical testing This missense variant replaces alanine with valine at codon 45 of the RET protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has not been reported as a germline mutation in individuals affected with hereditary cancer in the literature. This variant has been identified in 6/249804 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.

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