ClinVar Miner

Submissions for variant NM_000208.4(INSR):c.356C>T (p.Ala119Val)

gnomAD frequency: 0.00001  dbSNP: rs1347473020
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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Labcorp Genetics (formerly Invitae), Labcorp RCV002638095 SCV003521610 likely pathogenic not provided 2023-12-11 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 119 of the INSR protein (p.Ala119Val). This variant is present in population databases (no rsID available, gnomAD 0.003%). This missense change has been observed in individuals with clinical features of autosomal recessive INSR-related conditions (PMID: 12023989, 23824322; Invitae). This variant is also known as A92V. ClinVar contains an entry for this variant (Variation ID: 2200202). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt INSR protein function with a positive predictive value of 80%. Experimental studies have shown that this missense change affects INSR function (PMID: 12023989). In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.
PreventionGenetics, part of Exact Sciences RCV004538855 SCV004113972 uncertain significance INSR-related disorder 2023-05-05 criteria provided, single submitter clinical testing The INSR c.356C>T variant is predicted to result in the amino acid substitution p.Ala119Val. This variant has been reported in the compound heterozygous state or presumed compound heterozygous state in individuals with leprechaunism (also known as Donahue syndrome) (Reported as 356C>T, A92V, Patient FL-1, Longo et al. 2002. PubMed ID: 12023989; Patient 2, Grasso et al. 2013. PubMed ID: 23824322). This variant is reported in 0.0026% of alleles in individuals of European (Non-Finnish) descent in gnomAD (http://gnomad.broadinstitute.org/variant/19-7267652-G-A). While we suspect this variant is pathogenic, at this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.

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