Submissions for variant NM_000352.6(ABCC8):c.3107G>A (p.Trp1036Ter)

dbSNP: rs755259997

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Athena Diagnostics Inc	RCV000710378	SCV000840588	pathogenic	not provided	2018-08-14	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001174850	SCV001338240	pathogenic	Hyperinsulinemic hypoglycemia, familial, 1	2020-02-02	criteria provided, single submitter	clinical testing	Variant summary: ABCC8 c.3107G>A (p.Trp1036X) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. Truncations downstream of this position have been classified as pathogenic by our laboratory. The variant allele was found at a frequency of 4e-06 in 250932 control chromosomes. c.3107G>A has been reported in the literature in individuals affected with Congenital Hyperinsulinism who displayed a focal histology although the exact parent of origin or zygosity was not specified (Snider_2013). These data indicate that the variant is likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. One clinical diagnostic laboratory has submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation and classified the variant as pathogenic citing an overlapping evidence utilized in the context of this evaluation. Based on the evidence outlined above, the variant was classified as pathogenic.
Invitae	RCV000710378	SCV002233263	pathogenic	not provided	2023-05-08	criteria provided, single submitter	clinical testing	For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 585343). This variant is also known as p.Trp1037*. This premature translational stop signal has been observed in individual(s) with congenital hyperinsulinism (PMID: 23275527). This variant is present in population databases (rs755259997, gnomAD 0.0009%). This sequence change creates a premature translational stop signal (p.Trp1036*) in the ABCC8 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in ABCC8 are known to be pathogenic (PMID: 20685672, 23345197).
Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard	RCV001174850	SCV004026532	pathogenic	Hyperinsulinemic hypoglycemia, familial, 1	2023-08-16	criteria provided, single submitter	curation	The p.Trp1036Ter variant in ABCC8 has been reported in 4 individuals with hyperinsulinemic hypoglycemia (PMID: 23275527), and has been identified in 0.0009% (1/113312) of European (non-Finnish) chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP ID: rs755259997). 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: 585343) and has been interpreted as Pathogenic by Athena Diagnostics Inc, Invitae, and Women's Health and Genetics/Laboratory Corporation of America, LabCorp. Of the 4 affected individuals, all were compound heterozygotes that carried a reported pathogenic variants in trans, which increases the likelihood that the p.Trp1036Ter variant is pathogenic (PMID: 23275527). This nonsense variant leads to a premature termination codon at position 1036, which is predicted to lead to a truncated or absent protein. Loss of function of the ABCC8 gene is an established disease mechanism in autosomal recessive hyperinsulinemic hypoglycemia. In summary, this variant meets criteria to be classified as pathogenic for autosomal recessive hyperinsulinemic hypoglycemia. ACMG/AMP Criteria applied: PVS1, PM3_very-strong, PM2_supporting (Richards 2015).
Baylor Genetics	RCV003465648	SCV004208626	pathogenic	Type 2 diabetes mellitus	2023-01-04	criteria provided, single submitter	clinical testing
Clinical Genomics, Uppaluri K&H Personalized Medicine Clinic	RCV002251514	SCV002520766	uncertain significance	Maturity onset diabetes mellitus in young		flagged submission	research	Mutations in ABCC8 gene are associated with both neonatal diabetes mellitus as well as MODY. Patients with this mutation may have a better response to sulfonylureas. However, no sufficient evidence is found to ascertain the role of this particular variant (rs755259997) in MODY yet.
Clinical Genomics, Uppaluri K&H Personalized Medicine Clinic	RCV002251515	SCV002520767	uncertain significance	Transitory neonatal diabetes mellitus		flagged submission	research	Mutations in ABCC8 gene are associated with both neonatal diabetes mellitus as well as MODY. Patients with this mutation may have a better response to sulfonylureas. However, no sufficient evidence is found to ascertain the role of this particular variant (rs755259997) in neonatal diabetes yet.