ClinVar Miner

Submissions for variant NM_000208.4(INSR):c.2774T>C (p.Ile925Thr) (rs1599881881)

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Total submissions: 1
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
ARUP Laboratories, Molecular Genetics and Genomics,ARUP Laboratories RCV001001360 SCV001158558 likely pathogenic not specified 2019-06-18 criteria provided, single submitter clinical testing The INSR c.2774T>C; p.Ile925Thr variant, also known as p.Ile898Thr in the mature protein, is reported in the literature in an individual affected with leprechaunism, also known as Donahue syndrome (Longo 2002). This variant is absent from general population databases (Exome Variant Server, Genome Aggregation Database), indicating it is not a common polymorphism. The isoleucine at codon 925 is moderately conserved, but computational analyses (SIFT, PolyPhen-2) predict that this variant is deleterious. In agreement with these predictions, functional analyses indicate that p.Ile925Thr variant protein is poorly processed to its mature form (Hosoe 2017), and cultured cells expressing this variant exhibit significantly decreased insulin binding compared to cells expressing normal protein (Longo 2002). Based on available information, this variant is considered to be likely pathogenic. References: Hosoe J et al. Structural Basis and Genotype-Phenotype Correlations of INSR Mutations Causing Severe Insulin Resistance. Diabetes. 2017 Oct;66(10):2713-2723. Longo N et al. Genotype-phenotype correlation in inherited severe insulin resistance. Hum Mol Genet. 2002 Jun 1;11(12):1465-75.

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