Submissions for variant NM_000352.6(ABCC8):c.4322del (p.Pro1441fs)

dbSNP: rs758844607

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Counsyl	RCV000666204	SCV000790457	likely pathogenic	Hyperinsulinemic hypoglycemia, familial, 1	2017-03-21	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV001861751	SCV002215989	pathogenic	not provided	2023-05-02	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: 551208). This variant is also known as c.4325delC (p.Pro1442fs). This premature translational stop signal has been observed in individuals with autosomal recessive diffuse or focal hyperinsulinism (PMID: 20685672, 23275527). This variant is present in population databases (rs758844607, gnomAD 0.008%). This sequence change creates a premature translational stop signal (p.Pro1441Leufs*19) 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).
Clinical Genomics, Uppaluri K&H Personalized Medicine Clinic	RCV002245085	SCV002513330	uncertain risk allele	Maturity onset diabetes mellitus in young	2024-05-27	criteria provided, single submitter	research	This variant is found to be a potent moderate impact variant with a sufficient scientific evidence to support gene-disease correlation. However, since this is not a high impact variant and has no variant evidence, this variant is reclassified as Uncertain Risk Allele
Clinical Genomics, Uppaluri K&H Personalized Medicine Clinic	RCV004556810	SCV002513331	uncertain risk allele	Neonatal diabetes mellitus	2024-05-27	criteria provided, single submitter	research	This variant is found to be a potent moderate impact, variant with a sufficient scientific evidence of gene-disease correlation. However, since this is not a high impact variant and no variant evidence, this variant is reclassified as Uncertain risk allele.
Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard	RCV000666204	SCV004026503	pathogenic	Hyperinsulinemic hypoglycemia, familial, 1	2023-08-16	criteria provided, single submitter	curation	The p.Pro1441fs variant in ABCC8 has been previously reported in 3 individuals with hyperinsulinemic hypoglycemia and has been identified in 0.007% (1/13372) of African/African American chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP ID: rs758844607). 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#: 551208) and has been interpreted as likely pathogenic/pathogenic by Counsyl and Invitae, and as a variant of uncertain significance by Clinical Genomics (Uppaluri K&H Personalized Medicine Clinic). Of the 3 affected individuals, 1 was a compound heterozygote that carried a reported pathogenic variant in trans, which increases the likelihood that the p.Pro1441fs variant is pathogenic (PMID: 28442472). This variant is predicted to cause a frameshift, which alters the protein’s amino acid sequence beginning at position 1441 and leads to a premature termination codon 19 amino acids downstream. This alteration is then 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, PM2_supporting, PM3 (Richards 2015).
Baylor Genetics	RCV003465447	SCV004190413	pathogenic	Type 2 diabetes mellitus	2023-09-14	criteria provided, single submitter	clinical testing