Submissions for variant NM_000352.6(ABCC8):c.2666A>C (p.Lys889Thr)

gnomAD frequency: 0.00002  dbSNP: rs761862121

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Counsyl	RCV000675026	SCV000800454	uncertain significance	Hyperinsulinemic hypoglycemia, familial, 1	2018-06-07	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV001102596	SCV001259281	uncertain significance	Diabetes mellitus, transient neonatal, 2	2017-04-27	criteria provided, single submitter	clinical testing	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.
Illumina Laboratory Services, Illumina	RCV001107830	SCV001265014	uncertain significance	Permanent neonatal diabetes mellitus	2017-04-27	criteria provided, single submitter	clinical testing	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.
Illumina Laboratory Services, Illumina	RCV000675026	SCV001265015	uncertain significance	Hyperinsulinemic hypoglycemia, familial, 1	2017-04-27	criteria provided, single submitter	clinical testing	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.
Personalized Diabetes Medicine Program, University of Maryland School of Medicine	RCV001174391	SCV001337529	uncertain significance	Monogenic diabetes	2018-10-26	criteria provided, single submitter	research	ACMG criteria: PP3 (REVEL 0.763 + 8 predictors; not using BP4/2 predictors), PM2 (extremely low frequency in gnomAD)= VUS (Not using PS3- PMID:24814349/Saint Martin 2015 paper, it seems the functional studies aren't completely conclusive- it shows limited effect on channel activity (50% of WT compared to other mutations that maintained less than 85% of WT activity; "The K890T channel showed ~50% and ~70% of the WT response to MgADP and diazoxide, respectively, consistent with the reduced but significant activity in Rb efflux assays." Two cases PMID: 14764815 and PMID: 24814349 but not sure if phenotype is specific so not using PP4)
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001805796	SCV002051416	uncertain significance	not specified	2021-12-29	criteria provided, single submitter	clinical testing	Variant summary: ABCC8 c.2666A>C (p.Lys889Thr) results in a non-conservative amino acid change in 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 1.6e-05 in 251466 control chromosomes. c.2666A>C has been reported in the literature in a patient with diazoxide-unresponsive diffuse CHI carrying only the variant of interest (Bellanne-Chantelot_2010), as well as a patient with CHI carrying the variant in the homozygous state (Giurgea_2004). These data indicate that the variant may be associated with disease. In vitro expression studies testing traffic efficiency and responses of mutant channels to activation by MgADP and diazoxide showed the variant to have reduced but significant activity (Saint-Martin_2015). Three clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as VUS-possibly pathogenic.
Genetic Services Laboratory, University of Chicago	RCV001805796	SCV002066829	uncertain significance	not specified	2021-01-21	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV003465540	SCV004198433	likely pathogenic	Type 2 diabetes mellitus	2024-03-13	criteria provided, single submitter	clinical testing