Submissions for variant NM_000352.6(ABCC8):c.4411G>A (p.Asp1471Asn)

gnomAD frequency: 0.00001  dbSNP: rs72559716

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Counsyl	RCV000169299	SCV000220618	likely pathogenic	Hyperinsulinemic hypoglycemia, familial, 1	2014-08-21	criteria provided, single submitter	literature only
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000586940	SCV000696591	pathogenic	Familial hyperinsulinism	2016-02-17	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV000169299	SCV000914500	pathogenic	Hyperinsulinemic hypoglycemia, familial, 1	2018-11-01	criteria provided, single submitter	clinical testing	Across a selection of the available literature, the ABCC8 c.4411G>A (p.Asp1471Asn) missense variant, also referred to as c.4414G>A (p. Asp1472Asn), has been identified in12 individuals with hyperinsulinism, six in a compound heterozygous state and six in a heterozygous state (Giurgea et al. 2004; Henwood et al. 2005; Greer et al. 2007; Muzyamba et al. 2007; Brunetti-Pierri et al. 2008; Bellanné-Chantelot et al. 2009; Chandran et al. 2013; Kapoor et al. 2013; Xu et al. 2018). Muzyamba et al. (2007) reported a child with hyperinsulinism and focal disease who is heterozygous for two variants inherited from his father (p.Gly228Asp and p.Asp1471Asn) and one from his mother. The p.Gly228Asp and p.Asp1471Asn variants led to intracellular retention of the channel complex and loss of function, though it is unclear if one of these variants contributed to the loss of function alone. The p.Asp1471Asn variant was absent from 548 controls and is reported at a frequency of 0.00002 in the total population of the Genome Aggregation Database. Based on the collective evidence, the p.Asp1471Asn variant is classified as pathogenic for ABCC8-related disorders. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population.
Labcorp Genetics (formerly Invitae), Labcorp	RCV001385864	SCV001585867	pathogenic	not provided	2023-10-17	criteria provided, single submitter	clinical testing	This sequence change replaces aspartic acid, which is acidic and polar, with asparagine, which is neutral and polar, at codon 1471 of the ABCC8 protein (p.Asp1471Asn). 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 individual(s) with congenital hyperinsulinism (PMID: 17466004, 18988933, 30352420, 30354297). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. This variant is also known as c.G4414A (p.D1472N). ClinVar contains an entry for this variant (Variation ID: 188931). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be tolerated. Experimental studies have shown that this missense change affects ABCC8 function (PMID: 17466004, 30354297). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic.
Rady Children's Institute for Genomic Medicine, Rady Children's Hospital San Diego	RCV004545752	SCV001984815	pathogenic	ABCC8-related disorder	2020-08-10	criteria provided, single submitter	clinical testing	This variant has been previously reported as a heterozygous and compound heterozygous change in patients with ABCC8-related disorders (PMID: 30352420, 24616771, 23345197, 20685672, 18988933, 17466004, 15562009, 10720932). Functional characterization of the variant demonstrated loss of ATP-sensitive potassium channel function (PMID: 30354297). It is present in the heterozygous state in the gnomAD population database at a frequency of 0.002% (4/183574) and thus is presumed to be rare. The c.4411G>A (p.Asp1471Asn) variant is predicted by multiple in silico tools to have a deleterious effect on protein function. Based on the available evidence, the c.4411G>A (p.Asp1471Asn) variant is classified as Pathogenic.
Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard	RCV000169299	SCV004026579	pathogenic	Hyperinsulinemic hypoglycemia, familial, 1	2023-08-16	criteria provided, single submitter	curation	The p.Asp1471Asn variant in ABCC8 has been reported in at least 6 individuals with hyperinsulinemic hypoglycemia (PMID: 20685672, 30186238, 18988933, 24616771, 14764815, 17378627), and has been identified in 0.007% (1/13984) of East Asian chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs72559716). Although this variant has been seen in the general population in a heterozygous state, its frequency is low enough to be consistent with a recessive carrier frequency. This variant has also been reported in ClinVar (Variation ID#: 188931) and has been interpreted as pathogenic or likely pathogenic by multiple sources. Of the 6 affected individuals, 4 were compound heterozygotes that carried a reported pathogenic variant in trans, which increases the likelihood that the p.Asp1471Asn variant is pathogenic (Variation ID: 996301; PMID: 30186238, 18988933, 14764815, 17378627). In vitro functional studies provide some evidence that the p.Asp1471Asn variant may slightly impact protein function (PMID: 17466004). However, these types of assays may not accurately represent biological function. Computational prediction tools and conservation analyses suggest that this variant may impact the protein, though this information is not predictive enough to determine pathogenicity. One additional pathogenic variant, resulting in a different amino acid change at the same position, p.Asp1471His, has been reported in association with disease in ClinVar, supporting that a change at this position may not be tolerated (Variation ID: 1452717). In summary, this variant meets criteria to be classified as pathogenic for autosomal recessive hyperinsulinemic hypoglycemia. ACMG/AMP Criteria applied: PM3_very-strong, PM5, PP3, PS3_supporting, PP2_supporting (Richards 2015).
Baylor Genetics	RCV003468839	SCV004197210	pathogenic	Type 2 diabetes mellitus	2023-10-18	criteria provided, single submitter	clinical testing
Natera, Inc.	RCV001277177	SCV001464075	pathogenic	Hereditary hyperinsulinism	2020-09-16	no assertion criteria provided	clinical testing