ClinVar Miner

Submissions for variant NM_000352.6(ABCC8):c.313C>T (p.His105Tyr)

gnomAD frequency: 0.00003  dbSNP: rs766068851
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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Genetic Services Laboratory, University of Chicago RCV001817803 SCV002069233 likely pathogenic not provided 2018-08-09 criteria provided, single submitter clinical testing The c.313C>T sequence change occurs in exon 3 and results in an amino acid change, p.His105Tyr. The p.His105Tyr change affects a highly conserved amino acid residue located in a domain of the ABCC8 protein that is not known to be functional. The p.His105Tyr 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 hyperinsulinism, however, a different pathogenic sequence change affecting the same amino acid residue (p.His105Pro) has been described in a patient with ABCC8-related hyperinsulinism, in the compound heterozygous state with another pathogenic variant (Zhang et al., 2015. Gene 572(2):222-6). This sequence change has been described in the gnomAD database with a very low population frequency of 0.003% (dbSNP rs766068851). " DNA sequence analysis of the ABCC8 gene demonstrated a sequence change, c.313C>T, that occurs in exon 3 and results in an amino acid change, p.His105Tyr. The p.His105Tyr change affects a highly conserved amino acid residue located in a domain of the ABCC8 protein that is not known to be functional. The p.His105Tyr 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 hyperinsulinism, however, a different pathogenic sequence change affecting the same amino acid residue (p.His105Pro) has been described in a patient with ABCC8-related hyperinsulinism, in the compound heterozygous state with another pathogenic variant (Zhang et al., 2015. Gene 572(2):222-6). This sequence change has been described in the gnomAD database with a very low population frequency of 0.003% (dbSNP rs766068851).
GeneDx RCV001817803 SCV002757692 uncertain significance not provided 2022-11-22 criteria provided, single submitter clinical testing In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 31727138, 30193751, 33606663)
Revvity Omics, Revvity RCV001817803 SCV003824358 uncertain significance not provided 2022-10-14 criteria provided, single submitter clinical testing
Fulgent Genetics, Fulgent Genetics RCV005040401 SCV005676114 uncertain significance Diabetes mellitus, transient neonatal, 2; Hyperinsulinemic hypoglycemia, familial, 1; Leucine-induced hypoglycemia; Type 2 diabetes mellitus; Diabetes mellitus, permanent neonatal 3 2024-06-04 criteria provided, single submitter clinical testing
Labcorp Genetics (formerly Invitae), Labcorp RCV001817803 SCV005815988 uncertain significance not provided 2024-07-15 criteria provided, single submitter clinical testing This sequence change replaces histidine, which is basic and polar, with tyrosine, which is neutral and polar, at codon 105 of the ABCC8 protein (p.His105Tyr). This variant is present in population databases (rs766068851, gnomAD 0.02%). This variant has not been reported in the literature in individuals affected with ABCC8-related conditions. ClinVar contains an entry for this variant (Variation ID: 1338432). 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 with a positive predictive value of 95%. 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.
Department of Pathology and Laboratory Medicine, Sinai Health System RCV005361746 SCV005914842 uncertain significance Pulmonary arterial hypertension 2023-09-12 criteria provided, single submitter research

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