ClinVar Miner

Submissions for variant NM_000352.5(ABCC8):c.3989-9G>A (rs151344623)

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Total submissions: 8
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Athena Diagnostics Inc RCV000144995 SCV000612213 pathogenic not provided 2017-04-11 criteria provided, single submitter clinical testing
Counsyl RCV000009656 SCV000678147 pathogenic Persistent hyperinsulinemic hypoglycemia of infancy 2015-11-09 criteria provided, single submitter clinical testing
Division of Genomic Diagnostics,The Children's Hospital of Philadelphia RCV000144995 SCV000256803 pathogenic not provided 2015-10-07 no assertion criteria provided clinical testing
EGL Genetic Diagnostics,Eurofins Clinical Diagnostics RCV000144995 SCV000229594 pathogenic not provided 2014-06-13 criteria provided, single submitter clinical testing
Genetic Services Laboratory, University of Chicago RCV000144995 SCV000192031 pathogenic not provided 2013-07-23 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000590487 SCV000696590 pathogenic Familial hyperinsulinism 2017-06-05 criteria provided, single submitter clinical testing Variant summary: The ABCC8 variant, c.3989-9G>A (alternatively also known as 3992-9G>A) involves the alteration of a non-conserved intronic nucleotide in intron 32. Mutation taster predicts a disease-causing outcome for this variant. While Human Splicing Finder predicts this variant to form a cryptic splice acceptor site, other four splice prediction tools predict no significant impact on normal splicing. Functional study shows that this variant leads to aberrant splicing, resulting in a 7-bp addition, a 20-bp deletion, or 30-bp deletion of exon 32 that encodes NBF-2 (nucleotide binding fold 2) of the protein (Thomas_1995). This variant was found in 373/164074 control chromosomes including ExAC at a frequency of 0.0022734, which does not exceed the estimated maximal expected allele frequency of a pathogenic ABCC8 variant (0.0033541). This variant is a known common pathogenic variant causing congenital hyperinsulinism (CH). In Ashkenazi population, c.39899G>A and p.F1387del are the two most common CH-associated ABCC8 mutations (Nestorowicz_1998, Glaser_2011). Carrier rate of this mutation in Ashkenazi general population is 1:60 (Glaser_2011). In GeneReviews, proportion of familial CH attributed to these two mutations is estimated to be nearly 45%. Multiple clinical diagnostic laboratories/reputable databases have classified this variant as pathogenic. Taken together, this variant is classified as pathogenic.
Invitae RCV000144995 SCV000954424 pathogenic not provided 2018-12-19 criteria provided, single submitter clinical testing This sequence change falls in intron 32 of the ABCC8 gene. It does not directly change the encoded amino acid sequence of the ABCC8 protein. This variant is present in population databases (rs151344623, ExAC 0.03%). This variant has been observed to segregate with familial hyperinsulinism in several families and is considered a common pathogenic founder mutation (PMID: 7716548, 27754802, 8923011, 21716120). ClinVar contains an entry for this variant (Variation ID: 9088). Experimental studies have shown that this intronic change alters ABCC8 splicing (PMID: 7716548). For these reasons, this variant has been classified as Pathogenic.
OMIM RCV000009656 SCV000029874 pathogenic Persistent hyperinsulinemic hypoglycemia of infancy 1999-01-01 no assertion criteria provided literature only

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