Submissions for variant NM_000352.6(ABCC8):c.3877T>G (p.Tyr1293Asp)

gnomAD frequency: 0.00002  dbSNP: rs368710356

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Illumina Laboratory Services, Illumina	RCV001107655	SCV001264830	uncertain significance	Permanent neonatal diabetes mellitus	2018-01-13	criteria provided, single submitter	clinical testing	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease.
Illumina Laboratory Services, Illumina	RCV001107656	SCV001264831	uncertain significance	Diabetes mellitus, transient neonatal, 2	2018-01-13	criteria provided, single submitter	clinical testing	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease.
Illumina Laboratory Services, Illumina	RCV001107657	SCV001264832	uncertain significance	Hyperinsulinemic hypoglycemia, familial, 1	2018-01-13	criteria provided, single submitter	clinical testing	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease.
GeneDx	RCV001772324	SCV001992151	uncertain significance	not provided	2019-04-22	criteria provided, single submitter	clinical testing	Observed heterozygous in a patient with congenital hyperinsulinism who was also heterozygous for a variant in KCNJ11 in published literature; the unaffected father harbored both variants (Rozenkova et al., 2017); Functional studies show Y1293D may affect ABCC8 channel activation but additional experimentation is needed to understand significance (Rozenkova et al., 2017); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; This variant is associated with the following publications: (PMID: 29127764, 32041611)
MGZ Medical Genetics Center	RCV002290602	SCV002580675	uncertain significance	Type 2 diabetes mellitus	2022-01-21	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV001772324	SCV003467586	uncertain significance	not provided	2022-06-09	criteria provided, single submitter	clinical testing	This sequence change replaces tyrosine, which is neutral and polar, with aspartic acid, which is acidic and polar, at codon 1293 of the ABCC8 protein (p.Tyr1293Asp). This variant is present in population databases (rs368710356, gnomAD 0.006%). This missense change has been observed in individual(s) with ABCC8-related conditions (PMID: 29127764). ClinVar contains an entry for this variant (Variation ID: 879829). 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) performed at Invitae indicates that this missense variant is expected to disrupt ABCC8 protein function. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.