Submissions for variant NM_000352.6(ABCC8):c.4160_4162del (p.Phe1387del)

dbSNP: rs151344624

Total submissions: 14

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Eurofins Ntd Llc (ga)	RCV000201913	SCV000229685	pathogenic	not provided	2014-06-13	criteria provided, single submitter	clinical testing
Genetic Services Laboratory, University of Chicago	RCV000177757	SCV000592980	pathogenic	Hyperinsulinemic hypoglycemia, familial, 1	2015-10-21	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000587070	SCV000696588	pathogenic	Familial hyperinsulinism	2016-01-21	criteria provided, single submitter	clinical testing
Myriad Genetics, Inc.	RCV000177757	SCV001194064	pathogenic	Hyperinsulinemic hypoglycemia, familial, 1	2019-12-04	criteria provided, single submitter	clinical testing	NM_000352.3(ABCC8):c.4160_4162delTCT(F1387del) is classified as pathogenic in the context of ABCC8-related familial hyperinsulinism. Sources cited for classification include the following: PMID 9648840, 21716120, 9618169, 11999683, 11226335, 10447255 and 8923011. Classification of NM_000352.3(ABCC8):c.4160_4162delTCT(F1387del) is based on the following criteria: This is a well-established pathogenic variant in the literature that has been observed more frequently in patients with clinical diagnoses than in healthy populations. Please note: this variant was assessed in the context of healthy population screening.
Invitae	RCV000201913	SCV001582812	pathogenic	not provided	2023-12-27	criteria provided, single submitter	clinical testing	This variant, c.4160_4162del, results in the deletion of 1 amino acid(s) of the ABCC8 protein (p.Phe1387del), but otherwise preserves the integrity of the reading frame. This variant is present in population databases (rs771251369, gnomAD 0.04%). This variant has been observed in individuals with autosomal recessive hyperinsulinism and/or hyperinsulinism (PMID: 8923011, 9618169, 23275527). It has also been observed to segregate with disease in related individuals. This variant is also known as delF1388. ClinVar contains an entry for this variant (Variation ID: 196880). Algorithms developed to predict the effect of variants on protein structure and function are not available or were not evaluated for this variant. Experimental studies have shown that this variant affects ABCC8 function (PMID: 8923011, 11226335). For these reasons, this variant has been classified as Pathogenic.
Clinical Genomics, Uppaluri K&H Personalized Medicine Clinic	RCV002243862	SCV002513454	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 ( rs151344624 ) in neonatal diabetes yet.
Clinical Genomics, Uppaluri K&H Personalized Medicine Clinic	RCV002243861	SCV002513455	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 ( rs151344624) in MODY yet.
New York Genome Center	RCV000177757	SCV003925404	pathogenic	Hyperinsulinemic hypoglycemia, familial, 1	2022-02-08	criteria provided, single submitter	clinical testing
Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard	RCV000177757	SCV004026510	pathogenic	Hyperinsulinemic hypoglycemia, familial, 1	2023-08-16	criteria provided, single submitter	curation	The p.Phe1387del variant in ABCC8 has been reported in >10 individuals with hyperinsulinemic hypoglycemia (PMID: 11999683, 33861964, 23327786, 8923011, 9618169, 31997554, 9648840, 23275527), and has been identified in 0.06% (6/9450) of Ashkenazi Jewish chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs151344624). Although this variant has been seen in the general population in a heterozygous state, its frequency is not high enough to rule out a pathogenic role. This variant has also been reported in ClinVar (Variation ID: 196880) and has been interpreted as pathogenic by multiple sources. Of the many affected individuals, at least 7 were compound heterozygotes that carried a reported pathogenic variant in unknown phase, which increases the likelihood that the p.Phe1387del variant is pathogenic (Variation ID: 9088; PMID: 8923011). In vitro functional studies provide some evidence that the p.Phe1387del variant may impact protein function (PMID: 11226335, 8923011, 9648840). However, these types of assays may not accurately represent biological function. This variant is a deletion of 1 amino acid at position 1387 and is not predicted to alter the protein reading-frame. It is unclear if this deletion will impact the protein. In summary, this variant meets criteria to be classified as pathogenic for autosomal recessive hyperinsulinemic hypoglycemia. ACMG/AMP Criteria applied: PM3_very_strong, PS3, PM4_supporting (Richards 2015).
Baylor Genetics	RCV003462282	SCV004196548	pathogenic	Type 2 diabetes mellitus	2023-10-25	criteria provided, single submitter	clinical testing
PreventionGenetics, part of Exact Sciences	RCV003927651	SCV004740465	pathogenic	ABCC8-related condition	2024-02-13	criteria provided, single submitter	clinical testing	The ABCC8 c.4160_4162delTCT variant is predicted to result in an in-frame deletion (p.Phe1387del). This variant has been reported in the literature as delta F1388 and is a known founder variant within the Ashkenazi Jewish population (De Franco et al. 2020. PubMed ID: 32027066; Glaser et al. 1999. PubMed ID: 10447255). This variant has been documented in the homozygous and compound heterozygous states in many individuals with familial hyperinsulinism (Nestorowicz et al. 1996. PubMed ID: 8923011; Cartier et al. 2001. PubMed ID: 11226335; Nestorowicz et al. 1998. PubMed ID: 9618169). Functional analysis shows that this variant impacts both membrane trafficking and activity of the potassium channel (Cartier et al. 2001. PubMed ID: 11226335; Shyng et al. 1998. PubMed ID: 9648840). This variant is reported in 0.063% of alleles in individuals of Ashkenazi Jewish descent in gnomAD. This variant is interpreted as pathogenic.
OMIM	RCV000177757	SCV000029878	pathogenic	Hyperinsulinemic hypoglycemia, familial, 1	1996-11-01	no assertion criteria provided	literature only
Genomic Diagnostic Laboratory, Division of Genomic Diagnostics, Children's Hospital of Philadelphia	RCV000201913	SCV000256808	pathogenic	not provided	2015-10-07	no assertion criteria provided	clinical testing
Natera, Inc.	RCV001277181	SCV001464079	pathogenic	Hereditary hyperinsulinism	2020-09-16	no assertion criteria provided	clinical testing