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NM_000352.6(ABCC8):c.3661C>T (p.Arg1221Trp) AND Hyperinsulinemic hypoglycemia, familial, 1

Germline classification:
Uncertain significance (1 submission)
Last evaluated:
Sep 16, 2022
Review status:
1 star out of maximum of 4 stars
criteria provided, single submitter
Somatic classification
of clinical impact:
None
Review status:
(0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided
Somatic classification
of oncogenicity:
None
Review status:
(0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided
Record status:
current
Accession:
RCV003227950.2

Allele description [Variation Report for NM_000352.6(ABCC8):c.3661C>T (p.Arg1221Trp)]

NM_000352.6(ABCC8):c.3661C>T (p.Arg1221Trp)

Gene:
ABCC8:ATP binding cassette subfamily C member 8 [Gene - OMIM - HGNC]
Variant type:
single nucleotide variant
Cytogenetic location:
11p15.1
Genomic location:
Preferred name:
NM_000352.6(ABCC8):c.3661C>T (p.Arg1221Trp)
HGVS:
  • NC_000011.10:g.17398431G>A
  • NG_008867.1:g.83472C>T
  • NM_000352.6:c.3661C>TMANE SELECT
  • NM_001287174.3:c.3664C>T
  • NM_001351295.2:c.3727C>T
  • NM_001351296.2:c.3661C>T
  • NM_001351297.2:c.3658C>T
  • NP_000343.2:p.Arg1221Trp
  • NP_001274103.1:p.Arg1222Trp
  • NP_001338224.1:p.Arg1243Trp
  • NP_001338225.1:p.Arg1221Trp
  • NP_001338226.1:p.Arg1220Trp
  • LRG_790t1:c.3661C>T
  • LRG_790t2:c.3664C>T
  • LRG_790:g.83472C>T
  • LRG_790p1:p.Arg1221Trp
  • LRG_790p2:p.Arg1222Trp
  • NC_000011.9:g.17419978G>A
  • NM_000352.4:c.3661C>T
  • NR_147094.2:n.3810C>T
Protein change:
R1220W
Links:
dbSNP: rs567382793
NCBI 1000 Genomes Browser:
rs567382793
Molecular consequence:
  • NM_000352.6:c.3661C>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001287174.3:c.3664C>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001351295.2:c.3727C>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001351296.2:c.3661C>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001351297.2:c.3658C>T - missense variant - [Sequence Ontology: SO:0001583]
  • NR_147094.2:n.3810C>T - non-coding transcript variant - [Sequence Ontology: SO:0001619]
Observations:
1

Condition(s)

Name:
Hyperinsulinemic hypoglycemia, familial, 1 (HHF1)
Synonyms:
HYPERINSULINISM, FAMILIAL, WITH PANCREATIC NESIDIOBLASTOSIS; HYPOGLYCEMIA, HYPERINSULINEMIC, OF INFANCY; NESIDIOBLASTOSIS OF PANCREAS; See all synonyms [MedGen]
Identifiers:
MONDO: MONDO:0009734; MedGen: C2931832; Orphanet: 276575; Orphanet: 276598; OMIM: 256450

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Assertion and evidence details

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Submission AccessionSubmitterReview Status
(Assertion method)		Clinical Significance
(Last evaluated)		OriginMethodCitations
SCV003925307New York Genome Center
criteria provided, single submitter

(NYGC Assertion Criteria 2020)		Uncertain significance
(Sep 16, 2022) 		germlineclinical testing

Citation Link

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Summary from all submissions

EthnicityOriginAffectedIndividualsFamiliesChromosomes testedNumber TestedFamily historyMethod
not providedgermlineunknown1not providednot provided1not providedclinical testing

Details of each submission

From New York Genome Center, SCV003925307.2

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not provided1not providednot providedclinical testingnot provided

Description

The c.3661C>T p.(Arg1221Trp) variant in the ABCC8 gene has previously been reported in an individual with early onset diabetes (Proband P-6, age at diagnosis: 27 years, PMID: 33300273] and it has been deposited in ClinVar [ClinVar ID: 989961] as Variant of Uncertain Significance. The c.3661C>T variant is observed in 3 alleles (~0.0004% minor allele frequency with 0 homozygotes) in population databases (gnomAD v2.1.1 and v3.1.2, TOPMed Freeze8), suggesting it is not a common benign variant in the populations represented in those databases. The c.3661C>T variant in ABCC8 is located in exon 30 of this 39-exon gene, and predicted to replace an evolutionarily conserved arginine amino acid with tryptophan at position 1221 in the ABC transmembrane type-1 2 domainof the encoded protein. In silico predictions are in favor of damaging effect for p.(Arg1221Trp) [(CADD v1.6 = 32, REVEL = 0.736)]; however, there are no functional studies to support or refute these predictions. Based on available evidence this c.3661C>T p.(Arg1221Trp) variant identified in ABCC8 is classified as a Variant of Uncertain Significance.

#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineunknown1not providednot provided1not providednot providednot provided

Last Updated: Dec 22, 2024