Submissions for variant NM_000352.6(ABCC8):c.524T>A (p.Leu175Gln)

dbSNP: rs1554943599

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Counsyl	RCV000673404	SCV000798602	uncertain significance	Hyperinsulinemic hypoglycemia, familial, 1	2018-03-14	criteria provided, single submitter	clinical testing
Clinical Genomics, Uppaluri K&H Personalized Medicine Clinic	RCV002254173	SCV002524055	uncertain significance	Maturity onset diabetes mellitus in young		criteria provided, single submitter	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 ( rs1554943599) in MODY yet.
Clinical Genomics, Uppaluri K&H Personalized Medicine Clinic	RCV002254174	SCV002524056	uncertain significance	Transitory neonatal diabetes mellitus		criteria provided, single submitter	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 ( rs1554943599) in neonatal diabetes yet.
Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard	RCV000673404	SCV004026580	uncertain significance	Hyperinsulinemic hypoglycemia, familial, 1	2023-08-16	criteria provided, single submitter	curation	The p.Leu175Gln variant in ABCC8 has been previously reported in 1 individual with hyperinsulinemic hypoglycemia (PMID: 23275527), and has been seen in 0.001% (1/104792) of European (non-Finnish) chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP: rs1554943599). 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: 557284) and has been interpreted as a variant of uncertain significance by Counsyl and Clinical Genomics (Uppaluri K&H Personalized Medicine Clinic). Computational prediction tools and conservation analyses suggest that this variant may impact the protein, though this information is not predictive enough to determine pathogenicity. In summary, the clinical significance of the p.Leu175Gln variant is uncertain. ACMG/AMP Criteria applied: PP3, PM2_supporting (Richards 2015).
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV003489794	SCV004241441	uncertain significance	not specified	2023-12-14	criteria provided, single submitter	clinical testing	Variant summary: ABCC8 c.524T>A (p.Leu175Gln) results in a non-conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 4.3e-06 in 231976 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.524T>A has been reported in the literature in at-least one individual affected with Congenital Hyperinsulinism (example: Snider_2013). This report does not provide unequivocal conclusions about association of the variant with Congenital Hyperinsulinism. 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: 23275527). Two submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. All submitters classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.