Submissions for variant NM_000352.6(ABCC8):c.2835_2838del (p.Arg946fs)

dbSNP: rs1554913069

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Counsyl	RCV000673056	SCV000798222	likely pathogenic	Hyperinsulinemic hypoglycemia, familial, 1	2018-03-01	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000673056	SCV001361439	pathogenic	Hyperinsulinemic hypoglycemia, familial, 1	2019-11-29	criteria provided, single submitter	clinical testing	Variant summary: ABCC8 c.2835_2838delGAGA (p.Arg946LysfsX95) 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 (c.2992C>T (p.Arg998X), c.3574delG (p.Asp1192fsX16)). The variant was absent in 251486 control chromosomes (gnomAD). c.2835_2838delGAGA has been reported in the literature in individuals affected with Congenital Hyperinsulinism (CH)(Martinez_2016, 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. A ClinVar submission (evaluation after 2014) cites the variant as likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
GeneDx	RCV003151133	SCV003933575	pathogenic	not provided	2022-12-13	criteria provided, single submitter	clinical testing	Reported in association with congenital hyperinsulinism (Stanley et al., 2004; Martinez et al., 2016); Frameshift variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss of function is a known mechanism of disease; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 23275527, 14715863, 27188453)
Invitae	RCV003151133	SCV004295381	pathogenic	not provided	2023-09-08	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Arg946Lysfs*95) 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 not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individual(s) with congenital hyperinsulinism (PMID: 14715863, 23275527). ClinVar contains an entry for this variant (Variation ID: 556981). For these reasons, this variant has been classified as Pathogenic.
Clinical Genomics, Uppaluri K&H Personalized Medicine Clinic	RCV002251510	SCV002521949	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 ( rs1554913069) in MODY yet.
Clinical Genomics, Uppaluri K&H Personalized Medicine Clinic	RCV002251511	SCV002521951	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 ( rs1554913069) in neonatal diabetes yet.
Genetic Services Laboratory, University of Chicago	RCV003151133	SCV003839348	likely pathogenic	not provided	2022-10-16	no assertion criteria provided	clinical testing	DNA sequence analysis of the ABCC8 gene demonstrated two sequence changes. The first sequence change is a four base pair deletion in exon 24, c.2835_2838del. This likely pathogenic sequence change results in an amino acid frameshift and creates a premature stop codon 95 amino acids downstream of the change , p.Arg946Lysfs*95. This likely pathogenic sequence change is predicted to result in an abnormal transcript, which may be degraded, or may lead to the production of a truncated ABCC8 protein with potentially abnormal function. The c.2835_2838del sequence change has not been described in population databases such as ExAC and gnomAD. This sequence change has been reported in congenital hyperinsulinism (PMID: 14715863). This sequence change is the likely cause of this individual's phenotype, however functional studies have not been performed to prove this conclusively.