Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PM1PM2PP3_StrongPP5_Very_Strong
The NM_000352.6(ABCC8):c.674T>C(p.Leu225Pro) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★).
ABCC8 (HGNC:59): (ATP binding cassette subfamily C member 8) The protein encoded by this gene is a member of the superfamily of ATP-binding cassette (ABC) transporters. ABC proteins transport various molecules across extra- and intra-cellular membranes. ABC genes are divided into seven distinct subfamilies (ABC1, MDR/TAP, MRP, ALD, OABP, GCN20, White). This protein is a member of the MRP subfamily which is involved in multi-drug resistance. This protein functions as a modulator of ATP-sensitive potassium channels and insulin release. Mutations in the ABCC8 gene and deficiencies in the encoded protein have been observed in patients with hyperinsulinemic hypoglycemia of infancy, an autosomal recessive disorder of unregulated and high insulin secretion. Mutations have also been associated with non-insulin-dependent diabetes mellitus type II, an autosomal dominant disease of defective insulin secretion. Alternatively spliced transcript variants have been found for this gene. [provided by RefSeq, Jul 2020]
Verdict is Pathogenic. Variant got 16 ACMG points.
PM1
In a topological_domain Cytoplasmic (size 116) in uniprot entity ABCC8_HUMAN there are 12 pathogenic changes around while only 0 benign (100%) in NM_000352.6
PM2
Very rare variant in population databases, with high coverage;
PP3
MetaRNN computational evidence supports a deleterious effect, 0.954
PP5
Variant 11-17461731-A-G is Pathogenic according to our data. Variant chr11-17461731-A-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 21170.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing
Variant summary: ABCC8 c.674T>C (p.Leu225Pro) results in a non-conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 251496 control chromosomes. c.674T>C has been reported in the literature at a heterozygous state in multiple individuals affected with Neonatal Diabetes Mellitus (example, Masia_2007, Garcin_2020, Gopi_2021). These data indicate that the variant is likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function. The most pronounced variant effect results in about 4-fold over-activated current in Mg nucleotides in COS cells (Masia_2007). The following publications have been ascertained in the context of this evaluation (PMID: 32418263, 32893419, 17317760). ClinVar contains an entry for this variant (Variation ID: 21170). Based on the evidence outlined above, the variant was classified as pathogenic. -
Neonatal diabetes mellitus Pathogenic:1
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Molecular Genetics, Madras Diabetes Research Foundation
Significance: Likely pathogenic
Review Status: criteria provided, single submitter
Loss of stability (P = 0.0124);Loss of stability (P = 0.0124);Loss of stability (P = 0.0124);Loss of stability (P = 0.0124);Loss of stability (P = 0.0124);Loss of stability (P = 0.0124);Loss of stability (P = 0.0124);Loss of stability (P = 0.0124);