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 Inc	RCV000710379	SCV000840589	uncertain significance	not provided	2018-05-08	criteria provided, single submitter	clinical testing
Invitae	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	2021-01-05	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 (Foucan et al., 2018); In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 29216354)
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV003226376	SCV003922634	uncertain significance	not specified	2023-03-13	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 (gnomAD). 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 an obese child with a second pathogenic variant in the MC4R gene (example:Foucan_2018). These report(s) do not provide unequivocal conclusions about association of the variant with Familial Hyperinsulinism. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Seven clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 and classified the variant as VUS (n=3) and benign/likely benign (n=4). 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