Submissions for variant NM_000352.6(ABCC8):c.563A>G (p.Asn188Ser)

dbSNP: rs797045213

Total submissions: 11

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Genetic Services Laboratory, University of Chicago	RCV000192482	SCV000246304	pathogenic	Hyperinsulinemic hypoglycemia, familial, 1	2015-06-16	criteria provided, single submitter	clinical testing
Counsyl	RCV000192482	SCV000486836	likely pathogenic	Hyperinsulinemic hypoglycemia, familial, 1	2016-08-23	criteria provided, single submitter	clinical testing
Athena Diagnostics	RCV000517846	SCV000612223	pathogenic	not provided	2017-06-16	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000192482	SCV001361175	pathogenic	Hyperinsulinemic hypoglycemia, familial, 1	2019-06-03	criteria provided, single submitter	clinical testing	Variant summary: ABCC8 c.563A>G (p.Asn188Ser) results in a conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant was absent in 235752 control chromosomes (gnomAD). c.563A>G has been reported in the literature in multiple individuals affected with Congenital or Familial Hyperinsulinism (Shyng_1998, Nestorowicz_1998, Christesen_2001, Del Roio Liberatore_2015). These data indicate that the variant is very likely to be associated with disease. A functional study, Shyng_2008, found the variant to form channels that were indistinguishable from the wild-type in terms of regulation of the channel by nucleotides and diazoxide. However, the authors do indicate the variant could be playing a role in transcription, translation, trafficking or stability of protein, where were not assessed. Three ClinVar submissions from clinical diagnostic laboratories (evaluation after 2014) cites the variant as likely pathogenic/pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000517846	SCV002228414	pathogenic	not provided	2023-09-18	criteria provided, single submitter	clinical testing	This sequence change replaces asparagine, which is neutral and polar, with serine, which is neutral and polar, at codon 188 of the ABCC8 protein (p.Asn188Ser). For these reasons, this variant has been classified as Pathogenic. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. Experimental studies are conflicting or provide insufficient evidence to determine the effect of this variant on ABCC8 function (PMID: 9648840). 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. ClinVar contains an entry for this variant (Variation ID: 210082). This missense change has been observed in individual(s) with autosomal recessive diffuse or focal hyperinsulinism (PMID: 15562009, 16429405, 24434300, 24686051, 28442472). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. This variant is not present in population databases (gnomAD no frequency).
Genomic Medicine Center of Excellence, King Faisal Specialist Hospital and Research Centre	RCV003227708	SCV003924351	pathogenic	Diabetes mellitus, permanent neonatal 3	2023-05-08	criteria provided, single submitter	research
Baylor Genetics	RCV004567393	SCV005058628	likely pathogenic	Type 2 diabetes mellitus	2024-03-26	criteria provided, single submitter	clinical testing
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	RCV000192482	SCV005398939	pathogenic	Hyperinsulinemic hypoglycemia, familial, 1	2023-07-17	criteria provided, single submitter	clinical testing	Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0103 - Loss of function and gain of function are known mechanisms of disease in this gene and are associated with congenital hyperinsulism (CHI) and neonatal diabetes mellitus (NDM), respectively (PMIDs: 32376986, 32027066). (I) 0108 - This gene is known to be associated with both recessive and dominant disease. The ABCC8 gene has been associated with both autosomal recessive and dominant NDM and CHI (PMID: 32027066). Focal CHI is caused by a somatic second hit with the loss of the maternal chromosome 11p15.5 region by uniparental disomy that makes the paternally inherited variant mosaic homozygous (PMID: 32027066). (I) 0112 - The condition associated with this gene has incomplete penetrance. Variable penetrance has been reported for hyperinsulinemic hypoglycaemia, familial, 1 (MIM#256450) (PMID: 20301549). (I) 0200 - Variant is predicted to result in a missense amino acid change from asparagine to serine. (I) 0251 - This variant is heterozygous. (I) 0301 - Variant is absent from gnomAD (both v2 and v3). (SP) 0502 - Missense variant with conflicting in silico predictions and uninformative conservation. (I) 0600 - Variant is located in the annotated TMD0 domain (PMID: 25639667). (I) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. This variant has been reported multiple times as likely pathogenic and pathogenic, and have been observed in both homozygous and compound heterozygous individuals with hyperinsulinism (ClinVar, PMID: 25639667, PMID: 25972930, PMID: 15562009, PMID: 24686051). (SP) 1205 - This variant has been shown to be maternally inherited (by trio analysis). (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign
Fulgent Genetics, Fulgent Genetics	RCV005049469	SCV005676102	likely pathogenic	Diabetes mellitus, transient neonatal, 2; Hyperinsulinemic hypoglycemia, familial, 1; Leucine-induced hypoglycemia; Type 2 diabetes mellitus; Diabetes mellitus, permanent neonatal 3	2024-03-25	criteria provided, single submitter	clinical testing
3billion	RCV000192482	SCV005905380	pathogenic	Hyperinsulinemic hypoglycemia, familial, 1	2023-12-27	criteria provided, single submitter	clinical testing	The variant is not observed in the gnomAD v2.1.1 dataset. Predicted Consequence/Location: Missense variant In silico tool predictions suggest damaging effect of the variant on gene or gene product [3Cnet: 0.96 (>=0.6, sensitivity 0.72 and precision 0.9)]. Same nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000210082 /PMID: 9618169).The variant has been reported to be in trans with a pathogenic variant as either compound heterozygous or homozygous in at least 2 similarly affected unrelated individuals (PMID: 15562009, 24686051, 28442472, 9618169). Therefore, this variant is classified as Pathogenic according to the recommendation of ACMG/AMP guideline.
Natera, Inc.	RCV001833135	SCV002081151	pathogenic	Hereditary hyperinsulinism	2021-01-04	no assertion criteria provided	clinical testing