rs1260178539

Positions:

• chr11-17432240-GA-G

Variant summary

Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PVS1 PM2 PP5

The NM_000352.6(ABCC8):​c.1634del​(p.Phe545SerfsTer2) variant causes a frameshift change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000714 in 1,400,002 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 7.1e-7 (0 hom.)
• Consequence: ABCC8 NM_000352.6 frameshift
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:8 O:2
• Conservation: PhyloP100: 8.99

Genes affected

ABCC8 (HGNC:59): (ATP binding cassette subfamily C member 8) The protein encoded by this gene is a member of the superfamily of ATP-binding cassette (ABC) transporters. ABC proteins transport various molecules across extra- and intra-cellular membranes. ABC genes are divided into seven distinct subfamilies (ABC1, MDR/TAP, MRP, ALD, OABP, GCN20, White). This protein is a member of the MRP subfamily which is involved in multi-drug resistance. This protein functions as a modulator of ATP-sensitive potassium channels and insulin release. Mutations in the ABCC8 gene and deficiencies in the encoded protein have been observed in patients with hyperinsulinemic hypoglycemia of infancy, an autosomal recessive disorder of unregulated and high insulin secretion. Mutations have also been associated with non-insulin-dependent diabetes mellitus type II, an autosomal dominant disease of defective insulin secretion. Alternatively spliced transcript variants have been found for this gene. [provided by RefSeq, Jul 2020]

ACMG classification

Verdict is Pathogenic. Variant got 11 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 11-17432240-GA-G is Pathogenic according to our data. Variant chr11-17432240-GA-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 446765.We mark this variant Likely_pathogenic, oryginal submissions are: {Uncertain_risk_allele=2, Pathogenic=7}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ABCC8	NM_000352.6	c.1634del	p.Phe545SerfsTer2	frameshift_variant	11/39	ENST00000389817.8	NP_000343.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ABCC8	ENST00000389817.8	c.1634del	p.Phe545SerfsTer2	frameshift_variant	11/39	1	NM_000352.6	ENSP00000374467	P4

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD3 exomes AF: 0.00000633 AC: 1 AN: 157950 Hom.: 0 AF XY: 0.0000120 AC XY: 1 AN XY: 83072

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000403

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 7.14e-7 AC: 1 AN: 1400002 Hom.: 0 Cov.: 31 AF XY: 0.00000145 AC XY: 1 AN XY: 690550

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000280

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

Alfa AF: 0.0000936 Hom.: 0

Bravo AF: 0.00000378

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:8 Other:2

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Hyperinsulinemic hypoglycemia, familial, 1 Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Counsyl	Aug 22, 2017	- -
Pathogenic, criteria provided, single submitter	curation	Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard	Aug 16, 2023	The p.Phe545SerfsTer2 variant in ABCC8 has been previously reported in at least 2 individuals with hyperinsulinemic hypoglycemia (PMID: 16357843, 23275527), and has been identified in 0.002% (1/24796) of Latino/Admixed American chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP ID: rs1260178539). 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#: 446765) and has been interpreted as pathogenic by five sources. Of the 2 affected individuals, 1 was a compound heterozygote that carried a reported pathogenic variant in trans, which increases the likelihood that the p.Phe545SerfsTer2 variant is pathogenic (PMID: 16357843). This variant is predicted to cause a frameshift, which alters the protein’s amino acid sequence beginning at position 545 and leads to a premature termination codon 2 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, PM3, PM2_supporting (Richards 2015). -

not provided Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Athena Diagnostics	May 10, 2018	- -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Oct 10, 2022	This sequence change creates a premature translational stop signal (p.Phe545Serfs*2) 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). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This premature translational stop signal has been observed in individual(s) with focal congenital hyperinsulinism (PMID: 16357843). This variant is also known as 1631del t. ClinVar contains an entry for this variant (Variation ID: 446765). For these reasons, this variant has been classified as Pathogenic. -

Familial hyperinsulinism Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Jun 28, 2021

Variant summary: ABCC8 c.1634delT (p.Phe545SerfsX2) 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 6.3e-06 in 157950 control chromosomes (gnomAD). c.1634delT has been reported in the literature in individuals affected with Congenital Hyperinsulinism (example: Suchi_2006, Snider_2013). These data indicate that the variant may be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Two ClinVar submitters (evaluation after 2014) cite the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -

Type 2 diabetes mellitus Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Baylor Genetics

Jun 17, 2023

- -

Inborn genetic diseases Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Nov 23, 2020

The c.1634delT (p.F545Sfs*2) alteration, located in exon 11 (coding exon 11) of the ABCC8 gene, consists of a deletion of one nucleotide at position 1634, causing a translational frameshift with a predicted alternate stop codon after 2 amino acids. This alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. Based on the supporting evidence, this variant is unlikely to be causative of ABCC8-related diabetes mellitus; however, it would be expected to be causative of familial hyperinsulinemic hypoglycemia based on mechanism of disease. This mutation was identified in a cohort of individuals with congenital hyperinsulinism; however, details were limited (Snider, 2013). Based on the available evidence, this alteration is classified as pathogenic. -

Hereditary hyperinsulinism Pathogenic:1

Pathogenic, no assertion criteria provided

clinical testing

Natera, Inc.

Aug 23, 2021

- -

Neonatal diabetes mellitus Other:1

Uncertain risk allele, criteria provided, single submitter

research

Clinical Genomics, Uppaluri K&H Personalized Medicine Clinic

May 27, 2024

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. -

Maturity onset diabetes mellitus in young Other:1

Uncertain risk allele, criteria provided, single submitter

research

Clinical Genomics, Uppaluri K&H Personalized Medicine Clinic

May 27, 2024

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 -

Computational scores

Source: dbNSFP v4.3

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs1260178539; hg19: chr11-17453787;