Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PM2PP3_ModeratePP5
The NM_000352.6(ABCC8):c.1024G>T(p.Gly342Trp) variant causes a missense change. The variant allele was found at a frequency of 0.00000658 in 152,024 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).
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 Uncertain_significance. Variant got 5 ACMG points.
PM2
Very rare variant in population databases, with high coverage;
PP3
MetaRNN computational evidence supports a deleterious effect, 0.891
PP5
Variant 11-17453271-C-A is Pathogenic according to our data. Variant chr11-17453271-C-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 523360.We mark this variant Likely_pathogenic, oryginal submissions are: {Likely_pathogenic=1, Uncertain_significance=2}.
Centre for Mendelian Genomics, University Medical Centre Ljubljana
Significance: Likely pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing
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Maturity onset diabetes mellitus in young Uncertain:1
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Clinical Genomics, Uppaluri K&H Personalized Medicine Clinic
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: research
Mutations in ABCC8 gene are associated with both neonatal diabetes mellitus as well as MODY. Patients with this mutation may have a better response to sulfonylureas. However, no sufficient evidence is found to ascertain the role of this particular variant ( rs763028380) in MODY yet. -
Transitory neonatal diabetes mellitus Uncertain:1
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Clinical Genomics, Uppaluri K&H Personalized Medicine Clinic
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: research
Mutations in ABCC8 gene are associated with both neonatal diabetes mellitus as well as MODY. Patients with this mutation may have a better response to sulfonylureas. However, no sufficient evidence is found to ascertain the role of this particular variant ( rs763028380) in neonatal diabetes yet. -
Gain of ubiquitination at K337 (P = 0.0737);Gain of ubiquitination at K337 (P = 0.0737);Gain of ubiquitination at K337 (P = 0.0737);Gain of ubiquitination at K337 (P = 0.0737);.;.;.;Gain of ubiquitination at K337 (P = 0.0737);