Submissions for variant NM_000352.6(ABCC8):c.742C>T (p.Arg248Ter)

gnomAD frequency: 0.00001  dbSNP: rs72559730

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Athena Diagnostics Inc	RCV000710396	SCV000840608	pathogenic	not provided	2017-08-29	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001192814	SCV001361176	pathogenic	Hyperinsulinemic hypoglycemia, familial, 1	2019-01-31	criteria provided, single submitter	clinical testing	Variant summary: ABCC8 c.742C>T (p.Arg248X) 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. The variant allele was found at a frequency of 1.2e-05 in 246258 control chromosomes (gnomAD). c.742C>T has been reported in the literature in multiple individuals affected with Congenital Hyperinsulinism (Del Roio Liberatore_2015, Calabria_2012, Sandal_2009, FernndezMarmiesse_2006, Aguilar-Bryan_1999). These data indicate that the variant is very likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. A ClinVar submission from a clinical diagnostic laboratory (evaluation after 2014) cites the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Invitae	RCV000710396	SCV001583009	pathogenic	not provided	2023-09-12	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Arg248*) 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). This variant is present in population databases (rs72559730, gnomAD 0.003%). This premature translational stop signal has been observed in individual(s) with ABCC8-related conditions (PMID: 25972930, 27188453, 30191644, 30462810). ClinVar contains an entry for this variant (Variation ID: 585351). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. For these reasons, this variant has been classified as Pathogenic.
Fulgent Genetics, Fulgent Genetics	RCV002493256	SCV002802364	likely pathogenic	Diabetes mellitus, transient neonatal, 2; Hyperinsulinemic hypoglycemia, familial, 1; Leucine-induced hypoglycemia; Type 2 diabetes mellitus; Diabetes mellitus, permanent neonatal 3	2021-11-18	criteria provided, single submitter	clinical testing
Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard	RCV001192814	SCV004026575	pathogenic	Hyperinsulinemic hypoglycemia, familial, 1	2023-08-16	criteria provided, single submitter	curation	The p.Arg248Ter variant in ABCC8 has been reported in 10 individuals with hyperinsulinemic hypoglycemia (PMID: 10204114, 10828824, 16429405, 19475716, 23345197, 18767144, 20685672, 22855730, 27188453, 25972930, 30462810), and has been identified in 0.003% (1/30616) of South Asian chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP ID: rs72559730). 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: 585351) and has been interpreted as pathogenic by Athena Diagnostics Inc, Women's Health and Genetics/Laboratory Corporation of America (LabCorp), Invitae, and Natera (Inc.) and as likely pathogenic by Fulgent Genetics. Of the 10 affected individuals, 1 was a compound heterozygote that carried a reported pathogenic/likely pathogenic variant in trans, and 2 were homozygotes, which increases the likelihood that the p.Arg248Ter variant is pathogenic (Variation ID: 370210; PMID: 16429405, 20685672,22855730). This nonsense variant leads to a premature termination codon at position 248, 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_strong, PM2_supporting (Richards 2015).
Baylor Genetics	RCV003465649	SCV004199295	pathogenic	Type 2 diabetes mellitus	2023-09-28	criteria provided, single submitter	clinical testing
Natera, Inc.	RCV001825410	SCV002081118	pathogenic	Hereditary hyperinsulinism	2020-10-01	no assertion criteria provided	clinical testing