ClinVar Miner

Submissions for variant NM_000352.6(ABCC8):c.3290A>C (p.His1097Pro)

dbSNP: rs1352191146
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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Genetic Services Laboratory, University of Chicago RCV001817802 SCV002069232 likely pathogenic not provided 2018-08-09 criteria provided, single submitter clinical testing DNA sequence analysis of the ABCC8 gene demonstrated the presence of a sequence change, c.3290A>C, occurs exon 26 and results in an amino acid change, p.His1097Pro. The p.His1097Pro change affects a highly conserved amino acid residue located in a domain of the ABCC8 protein that is known to be functional. The p.His1097Pro substitution appears to be deleterious using several in-silico pathogenicity prediction tools (SIFT, PolyPhen2, REVEL). This particular amino acid change does not appear to have been described in the literature in other patients with ABCC8-related disorders. This sequence change has been described in the gnomAD database with a very low population frequency of 0.0004%.
Labcorp Genetics (formerly Invitae), Labcorp RCV001817802 SCV002112589 uncertain significance not provided 2021-09-17 criteria provided, single submitter clinical testing This sequence change replaces histidine with proline at codon 1097 of the ABCC8 protein (p.His1097Pro). The histidine residue is highly conserved and there is a moderate physicochemical difference between histidine and proline. This variant is not present in population databases (ExAC no frequency). This variant has not been reported in the literature in individuals affected with ABCC8-related conditions. 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 ABCC8 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.
Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard RCV003321874 SCV004026597 uncertain significance Hyperinsulinemic hypoglycemia, familial, 1 2023-08-16 criteria provided, single submitter curation The p.His1097Pro variant in ABCC8 has not been previously reported in the literature in individuals with hyperinsulinemic hypoglycemia, but has been seen in 0.003% (1/34574) of Latino/Admixed American chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP: rs1352191146). Although this variant has been seen in the general population in a heterozygous state, its frequency is low enough to be consistent with a recessive carrier frequency. This variant has also been reported in ClinVar (Variation ID: 1338431) and has been interpreted as likely pathogenic by Genetic Services Laboratory (University of Chicago) and as a variant of uncertain significance by Invitae. Computational prediction tools and conservation analyses suggest that this variant may impact the protein, though this information is not predictive enough to determine pathogenicity. In summary, the clinical significance of the p.His1097Pro variant is uncertain. ACMG/AMP Criteria applied: PP3, PM2_supporting (Richards 2015).
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV004526149 SCV005040073 uncertain significance not specified 2024-03-07 criteria provided, single submitter clinical testing Variant summary: ABCC8 c.3290A>C (p.His1097Pro) results in a non-conservative amino acid change located in the ABC transporter type 1, transmembrane domain (IPR011527) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 4e-06 in 251238 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. To our knowledge, no occurrence of c.3290A>C in individuals affected with Familial Hyperinsulinism and no experimental evidence demonstrating its impact on protein function have been reported. ClinVar contains an entry for this variant (Variation ID: 1338431). Based on the evidence outlined above, the variant was classified as uncertain significance.

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