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NM_001374385.1(ATP8B1):c.1982T>C (p.Ile661Thr) AND Progressive familial intrahepatic cholestasis

Germline classification:
Pathogenic (1 submission)
Last evaluated:
Feb 4, 2023
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:
RCV003155019.1

Allele description [Variation Report for NM_001374385.1(ATP8B1):c.1982T>C (p.Ile661Thr)]

NM_001374385.1(ATP8B1):c.1982T>C (p.Ile661Thr)

Gene:
ATP8B1:ATPase phospholipid transporting 8B1 [Gene - OMIM - HGNC]
Variant type:
single nucleotide variant
Cytogenetic location:
18q21.31
Genomic location:
Preferred name:
NM_001374385.1(ATP8B1):c.1982T>C (p.Ile661Thr)
HGVS:
  • NC_000018.10:g.57669433A>G
  • NG_007148.3:g.139390T>C
  • NM_001374385.1:c.1982T>CMANE SELECT
  • NM_001374386.1:c.1832T>C
  • NM_005603.6:c.1982T>C
  • NP_001361314.1:p.Ile661Thr
  • NP_001361315.1:p.Ile611Thr
  • NP_005594.1:p.Ile661Thr
  • NP_005594.2:p.Ile661Thr
  • LRG_1205t1:c.1982T>C
  • LRG_1205:g.139390T>C
  • LRG_1205p1:p.Ile661Thr
  • NC_000018.9:g.55336665A>G
  • NM_005603.4:c.1982T>C
  • NM_005603.5:c.1982T>C
  • O43520:p.Ile661Thr
Protein change:
I611T; ILE661THR
Links:
UniProtKB: O43520#VAR_008812; OMIM: 602397.0006; dbSNP: rs121909100
NCBI 1000 Genomes Browser:
rs121909100
Molecular consequence:
  • NM_001374385.1:c.1982T>C - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001374386.1:c.1832T>C - missense variant - [Sequence Ontology: SO:0001583]
  • NM_005603.6:c.1982T>C - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Name:
Progressive familial intrahepatic cholestasis (PFIC)
Synonyms:
Progressive intrahepatic cholestasis; Progressive family intrahepatic cholestasis
Identifiers:
MONDO: MONDO:0015762; MedGen: C0268312; OMIM: PS211600

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Assertion and evidence details

Help
Submission AccessionSubmitterReview Status
(Assertion method)		Clinical Significance
(Last evaluated)		OriginMethodCitations
SCV003844340Women's Health and Genetics/Laboratory Corporation of America, LabCorp
criteria provided, single submitter

(LabCorp Variant Classification Summary - May 2015)		Pathogenic
(Feb 4, 2023) 		germlineclinical testing

PubMed (4)
[See all records that cite these PMIDs]

Citation Link

Help

Summary from all submissions

EthnicityOriginAffectedIndividualsFamiliesChromosomes testedNumber TestedFamily historyMethod
not providedgermlineunknownnot providednot providednot providednot providednot providedclinical testing

Citations

PubMed

Characterization of mutations in ATP8B1 associated with hereditary cholestasis.

Klomp LW, Vargas JC, van Mil SW, Pawlikowska L, Strautnieks SS, van Eijk MJ, Juijn JA, Pabón-Peña C, Smith LB, DeYoung JA, Byrne JA, Gombert J, van der Brugge G, Berger R, Jankowska I, Pawlowska J, Villa E, Knisely AS, Thompson RJ, Freimer NB, Houwen RH, Bull LN.

Hepatology. 2004 Jul;40(1):27-38.

PubMed [citation]
PMID:
15239083

Impact of Genotype, Serum Bile Acids, and Surgical Biliary Diversion on Native Liver Survival in FIC1 Deficiency.

van Wessel DBE, Thompson RJ, Gonzales E, Jankowska I, Shneider BL, Sokal E, Grammatikopoulos T, Kadaristiana A, Jacquemin E, Spraul A, Lipiński P, Czubkowski P, Rock N, Shagrani M, Broering D, Algoufi T, Mazhar N, Nicastro E, Kelly D, Nebbia G, Arnell H, Fischler B, et al.

Hepatology. 2021 Aug;74(2):892-906. doi: 10.1002/hep.31787. Epub 2021 Jul 13.

PubMed [citation]
PMID:
33666275
PMCID:
PMC8456904
See all PubMed Citations (4)

Details of each submission

From Women's Health and Genetics/Laboratory Corporation of America, LabCorp, SCV003844340.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (4)

Description

Variant summary: ATP8B1 c.1982T>C (p.Ile661Thr) results in a non-conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 9.6e-05 in 251022 control chromosomes. This frequency is not significantly higher than estimated for a pathogenic variant in ATP8B1 causing Familial Intrahepatic Cholestasis (9.6e-05 vs 0.0022), allowing no conclusion about variant significance. c.1982T>C has been reported in the literature as a homozygous or compound heterozygous genotype in multiple individuals affected with Familial Intrahepatic Cholestasis (example, PMID: 19731236, 15239083, 9918928, 33666275). These data indicate that the variant is very likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function (example, PMID: 19731236). The most pronounced variant effect results in decreased protein stability/overall reduced protein expression compared to wild type. Five clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation (Pathogenic, n=4). Based on the evidence outlined above, the variant was classified as pathogenic.

#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineunknownnot providednot providednot providednot providednot providednot providednot provided

Last Updated: Nov 24, 2024