Submissions for variant NM_000352.6(ABCC8):c.3784G>A (p.Ala1262Thr)

gnomAD frequency: 0.00001  dbSNP: rs1266053680

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Athena Diagnostics	RCV000991472	SCV001142889	uncertain significance	not provided	2019-12-16	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV000991472	SCV001400597	likely pathogenic	not provided	2023-07-10	criteria provided, single submitter	clinical testing	This sequence change replaces alanine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 1262 of the ABCC8 protein (p.Ala1262Thr). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This missense change has been observed in individuals with atypical familial hyperinsulinemia, being paternally inherited (PMID: 21981106, 26092864). This variant is also known as A1263T. ClinVar contains an entry for this variant (Variation ID: 804492). 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) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on ABCC8 protein function. Experimental studies have shown that this missense change affects ABCC8 function (PMID: 26092864). In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.
Department Of Endocrinology, Sanjay Gandhi Postgraduate Institute Of Medical Sciences	RCV003329118	SCV004031467	likely pathogenic	Maturity onset diabetes mellitus in young	2023-08-15	criteria provided, single submitter	clinical testing	A heterozygous missense variation in exon 31 of the ABCC8 gene (chr11:g.17419314C>T; c.3784G>A) that results in the amino acid substitution of Threonine (neutral, polar) for Alanine (neutral, non polar) at codon 1262 (p.Ala1262Thr) was detected. The variant affects the 'ABC transmembrane type-1' domain of ABCC8 which has 57 missense/in-frame variants reported, none of which are classified as benign. Experimental studies have shown that this missense change affects ABCC8 function (PMID: 26092864). The variant is absent in 1000 genome database and has a frequency of 0.000013 in gnomAD genomes. The variant was determined to be damaging by Mutation taster 2 and SIFT, and probably damaging by PolyPhen2. PM1, PM2, PP2, PP3.
Neuberg Centre For Genomic Medicine, NCGM	RCV004577347	SCV005042595	pathogenic	Hyperinsulinemic hypoglycemia, familial, 1		criteria provided, single submitter	clinical testing	The missense c.3784G>Ap.Ala1262Thr variant in ABCC8 gene has been reported previously in heterozygous state in multiple individuals affected with diabetes/hyperinsulinism Jayakrishnan C, et. al., 2022; Nessa A, et. al., 2015. Experimental studies have shown that this missense change affects ABCC8 function Nessa A, et. al., 2015. The p.Ala1262Thr variant has been reported with allele frequency of 0.0004% in gnomAD Exomes and is novel not in any individuals in 1000 Genomes. This variant has been reported to the ClinVar database as Uncertain Significance / Likely Pathogenic. The amino acid change p.Ala1262Thr in ABCC8 is predicted as conserved by GERP++ and PhyloP across 100 vertebrates. The amino acid Ala at position 1262 is changed to a Thr changing protein sequence and it might alter its composition and physico-chemical properties. For these reasons, this variant has been classified as Pathogenic.