Submissions for variant NM_000352.6(ABCC8):c.3203C>T (p.Thr1068Met)

gnomAD frequency: 0.00102  dbSNP: rs139524121

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Athena Diagnostics	RCV000710379	SCV000840589	uncertain significance	not provided	2018-05-08	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV000710379	SCV001019604	likely benign	not provided	2024-01-29	criteria provided, single submitter	clinical testing
Mendelics	RCV000988490	SCV001138232	likely benign	Hyperinsulinemic hypoglycemia, familial, 1	2019-05-28	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV001104124	SCV001260963	likely benign	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 and internal cut-off values, a variant classified as likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease.
Illumina Laboratory Services, Illumina	RCV000988490	SCV001260964	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.
Illumina Laboratory Services, Illumina	RCV001104429	SCV001261295	benign	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 and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease.
GeneDx	RCV000710379	SCV001988336	uncertain significance	not provided	2024-11-07	criteria provided, single submitter	clinical testing	Reported in a patient with obesity in published literature; however this patient was noted to have a different molecular cause for the phenotype (PMID: 29216354); In silico analysis indicates that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 35982159, 29216354)
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV003226376	SCV003922634	uncertain significance	not specified	2024-07-12	criteria provided, single submitter	clinical testing	Variant summary: ABCC8 c.3203C>T (p.Thr1068Met) results in a non-conservative amino acid change located in the ABC transporter type 1, transmembrane domain (IPR011527) of the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.00022 in 251452 control chromosomes, predominantly at a frequency of 0.0028 within the African or African-American subpopulation in the gnomAD database. This frequency is not significantly higher than estimated for a pathogenic variant in ABCC8 causing Familial Hyperinsulinism (0.00022 vs 0.0034), allowing no conclusion about variant significance. c.3203C>T has been reported in the literature in a child of Afro-Caribbean ancestry affected with obesity who also harbored a pathogenic variant in the MC4R gene (Foucan_2018). This report does not provide unequivocal conclusions about association of the variant with Familial Hyperinsulinism or other ABCC8-related disorders. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publication has been ascertained in the context of this evaluation (PMID: 29216354). ClinVar contains an entry for this variant (Variation ID: 585344). Based on the evidence outlined above, the variant was classified as uncertain significance.
CeGaT Center for Human Genetics Tuebingen	RCV000710379	SCV004136030	uncertain significance	not provided	2023-02-01	criteria provided, single submitter	clinical testing