ClinVar Miner

Submissions for variant NM_020975.6(RET):c.308A>G (p.His103Arg)

gnomAD frequency: 0.00003  dbSNP: rs375390467
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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Labcorp Genetics (formerly Invitae), Labcorp RCV000196485 SCV000255053 uncertain significance Multiple endocrine neoplasia, type 2 2023-12-01 criteria provided, single submitter clinical testing This sequence change replaces histidine, which is basic and polar, with arginine, which is basic and polar, at codon 103 of the RET protein (p.His103Arg). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This variant has not been reported in the literature in individuals affected with RET-related conditions. ClinVar contains an entry for this variant (Variation ID: 216724). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Not Available"; PolyPhen-2: "Benign"; Align-GVGD: "Not Available". The arginine 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.
Counsyl RCV000409523 SCV000490053 uncertain significance Multiple endocrine neoplasia type 2B 2016-10-18 criteria provided, single submitter clinical testing
Counsyl RCV000411052 SCV000490054 uncertain significance Multiple endocrine neoplasia type 2A 2016-10-18 criteria provided, single submitter clinical testing
Ambry Genetics RCV002321798 SCV002606363 likely benign Hereditary cancer-predisposing syndrome 2022-09-26 criteria provided, single submitter clinical testing This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, 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.
All of Us Research Program, National Institutes of Health RCV000196485 SCV004832863 uncertain significance Multiple endocrine neoplasia, type 2 2023-10-27 criteria provided, single submitter clinical testing This missense variant replaces histidine with arginine at codon 103 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 in individuals affected with RET-related disorders in the literature. This variant has been identified in 1/234344 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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