This sequence change replaces isoleucine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 661 of the ATP8B1 protein (p.Ile661Thr). This variant is present in population databases (rs121909100, gnomAD 0.02%). This missense change has been observed in individuals with benign recurrent intrahepatic cholestasis and/or progressive familial intrahepatic cholestasis (PMID: 9500542, 9918928, 15239083, 20232290, 33666275, 34016879). ClinVar contains an entry for this variant (Variation ID: 7267). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt ATP8B1 protein function with a negative predictive value of 80%. Experimental studies have shown that this missense change affects ATP8B1 function (PMID: 19731236, 19918981). For these reasons, this variant has been classified as Pathogenic.
ClinVar Genomic variation as it relates to human health
NM_001374385.1(ATP8B1):c.1982T>C (p.Ile661Thr)
Germline
Classification
Help
The aggregate germline classification for this variant, typically for a monogenic or Mendelian disorder as in the ACMG/AMP guidelines, or for response to a drug. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the aggregate classification.
(15)
Help
Stars represent the aggregate review status, or the level of review supporting the aggregate germline classification for this VCV record. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. The number of submissions which contribute to this review status is shown in parentheses.
Pathogenic/Likely pathogenic
15
criteria provided, multiple submitters, no conflicts
Somatic
No data submitted for somatic clinical impact
Somatic
No data submitted for oncogenicity
Variant Details
- Identifiers
-
NM_001374385.1(ATP8B1):c.1982T>C (p.Ile661Thr)
Variation ID: 7267 Accession: VCV000007267.29
- Type and length
-
single nucleotide variant, 1 bp
- Location
-
Cytogenetic: 18q21.31 18: 57669433 (GRCh38) [ NCBI UCSC ] 18: 55336665 (GRCh37) [ NCBI UCSC ]
- Timeline in ClinVar
-
First in ClinVar Help The date this variant first appeared in ClinVar with each type of classification.
Last submission Help The date of the most recent submission for each type of classification for this variant.
Last evaluated Help The most recent date that a submitter evaluated this variant for each type of classification.
Germline Mar 24, 2015 Oct 8, 2024 Mar 24, 2024 - HGVS
-
... more HGVS ... less HGVSNucleotide Protein Molecular
consequenceNM_001374385.1:c.1982T>C MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_001361314.1:p.Ile661Thr missense NM_001374386.1:c.1832T>C NP_001361315.1:p.Ile611Thr missense NM_005603.6:c.1982T>C NP_005594.2:p.Ile661Thr missense NC_000018.10:g.57669433A>G NC_000018.9:g.55336665A>G NG_007148.3:g.139390T>C LRG_1205:g.139390T>C LRG_1205t1:c.1982T>C LRG_1205p1:p.Ile661Thr O43520:p.Ile661Thr NP_005594.1:p.Ile661Thr - Protein change
- I661T, I611T
- Other names
- -
- Canonical SPDI
- NC_000018.10:57669432:A:G
-
Functional
consequence HelpThe effect of the variant on RNA or protein function, based on experimental evidence from submitters.
- -
-
Global minor allele
frequency (GMAF) HelpThe global minor allele frequency calculated by the 1000 Genomes Project. The minor allele at this location is indicated in parentheses and may be different from the allele represented by this VCV record.
- -
-
Allele frequency
Help
The frequency of the allele represented by this VCV record.
-
Exome Aggregation Consortium (ExAC) 0.00009
The Genome Aggregation Database (gnomAD) 0.00009
The Genome Aggregation Database (gnomAD), exomes 0.00010
Trans-Omics for Precision Medicine (TOPMed) 0.00010
NHLBI Exome Sequencing Project (ESP) Exome Variant Server 0.00015
- Links
Genes
| Gene | OMIM | ClinGen Gene Dosage Sensitivity Curation |
Variation Viewer
Help
Links to Variation Viewer, a genome browser to view variation data from NCBI databases. |
Related variants | ||
|---|---|---|---|---|---|---|
| HI score
Help
The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
TS score
Help
The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
Within gene
Help
The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants. |
All
Help
The number of variants in ClinVar for this gene, including smaller variants within the gene and larger CNVs that overlap or fully contain the gene. |
|||
| ATP8B1 | - | - |
GRCh38 GRCh37 |
541 | 1128 | |
Conditions - Germline
| Condition
Help
The condition for this variant-condition (RCV) record in ClinVar. |
Classification
Help
The aggregate germline classification for this variant-condition (RCV) record in ClinVar. The number of submissions that contribute to this aggregate classification is shown in parentheses. (# of submissions) |
Review status
Help
The aggregate review status for this variant-condition (RCV) record in ClinVar. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. |
Last evaluated
Help
The most recent date that a submitter evaluated this variant for the condition. |
Variation/condition record
Help
The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page. |
|---|---|---|---|---|
| Pathogenic (3) |
criteria provided, multiple submitters, no conflicts
|
Mar 24, 2024 | RCV000007689.10 | |
| Pathogenic/Likely pathogenic (4) |
criteria provided, multiple submitters, no conflicts
|
Jun 19, 2023 | RCV000007690.14 | |
| Pathogenic (6) |
criteria provided, multiple submitters, no conflicts
|
Feb 6, 2024 | RCV000723736.14 | |
| Pathogenic (1) |
criteria provided, single submitter
|
Feb 4, 2023 | RCV003155019.1 | |
|
ATP8B1-related disorder
|
Pathogenic (1) |
no assertion criteria provided
|
Feb 13, 2024 | RCV004547464.2 |
Submissions - Germline
| Classification
Help
The submitted germline classification for each SCV record. (Last evaluated) |
Review status
Help
Stars represent the review status, or the level of review supporting the submitted (SCV) record. This value is calculated by NCBI based on data from the submitter. Read our rules for calculating the review status. This column also includes a link to the submitter’s assertion criteria if provided, and the collection method. (Assertion criteria) |
Condition
Help
The condition for the classification, provided by the submitter for this submitted (SCV) record. This column also includes the affected status and allele origin of individuals observed with this variant. |
Submitter
Help
The submitting organization for this submitted (SCV) record. This column also includes the SCV accession and version number, the date this SCV first appeared in ClinVar, and the date that this SCV was last updated in ClinVar. |
More information
Help
This column includes more information supporting the classification, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter. |
|
|---|---|---|---|---|---|
|
Pathogenic
(Jun 03, 2016)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: unknown
Allele origin:
germline
|
Eurofins Ntd Llc (ga)
Accession: SCV000331489.4
First in ClinVar: Dec 06, 2016 Last updated: Dec 15, 2018 |
Number of individuals with the variant: 3
Zygosity: Homozygote, Single Heterozygote
Sex: mixed
|
|
|
Pathogenic
(May 13, 2022)
|
criteria provided, single submitter
Method: clinical testing
|
Benign recurrent intrahepatic cholestasis type 1
Affected status: yes
Allele origin:
germline
|
MGZ Medical Genetics Center
Accession: SCV002580065.1
First in ClinVar: Oct 15, 2022 Last updated: Oct 15, 2022
Comment:
ACMG criteria applied: PM3_STR, PS3_MOD, PS4_MOD, PM2_SUP, PP4
|
Number of individuals with the variant: 1
Sex: female
|
|
|
Likely pathogenic
(Jun 19, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
Progressive familial intrahepatic cholestasis type 1
Affected status: unknown
Allele origin:
unknown
|
Mendelics
Accession: SCV001140912.2
First in ClinVar: Jan 09, 2020 Last updated: Jun 24, 2023 |
|
|
|
Pathogenic
(Jul 03, 2019)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: unknown
Allele origin:
germline
|
Revvity Omics, Revvity
Accession: SCV002022083.3
First in ClinVar: Nov 29, 2021 Last updated: Feb 04, 2024 |
|
|
|
Pathogenic
(Feb 06, 2024)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: unknown
Allele origin:
germline
|
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital
Accession: SCV004242942.1
First in ClinVar: Feb 14, 2024 Last updated: Feb 14, 2024 |
|
|
|
Pathogenic
(Dec 25, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: unknown
Allele origin:
germline
|
Labcorp Genetics (formerly Invitae), Labcorp
Accession: SCV004265336.1
First in ClinVar: Feb 14, 2024 Last updated: Feb 14, 2024 |
Comment:
This sequence change replaces isoleucine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 661 of the ATP8B1 protein (p.Ile661Thr). … (more)
This sequence change replaces isoleucine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 661 of the ATP8B1 protein (p.Ile661Thr). This variant is present in population databases (rs121909100, gnomAD 0.02%). This missense change has been observed in individuals with benign recurrent intrahepatic cholestasis and/or progressive familial intrahepatic cholestasis (PMID: 9500542, 9918928, 15239083, 20232290, 33666275, 34016879). ClinVar contains an entry for this variant (Variation ID: 7267). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt ATP8B1 protein function with a negative predictive value of 80%. Experimental studies have shown that this missense change affects ATP8B1 function (PMID: 19731236, 19918981). For these reasons, this variant has been classified as Pathogenic. (less)
|
|
|
Pathogenic
(Oct 16, 2018)
|
criteria provided, single submitter
Method: clinical testing
|
Progressive familial intrahepatic cholestasis type 1
Affected status: unknown
Allele origin:
germline
|
Illumina Laboratory Services, Illumina
Accession: SCV000914821.1
First in ClinVar: May 27, 2019 Last updated: May 27, 2019 |
Comment:
Across a selection of available literature, the ATP8B1 c.1982T>C (p.Ile661Thr) variant has been reported in a homozygous state in 25 probands, in a compound heterozygous … (more)
Across a selection of available literature, the ATP8B1 c.1982T>C (p.Ile661Thr) variant has been reported in a homozygous state in 25 probands, in a compound heterozygous state in eight probands and in a heterozygous state in nine probands (Bull et al. 1998; Tygstrup et al. 1999; Klomp et al. 2004). The clinical presentation of many probands with this variant were described as having benign recurrent intrahepatic cholestatis, but some were described to have progressive disease. This disease has been noted to have reduced penetrance, and five individuals homozygous for the p.Ile661Thr variant were asymptomatic (Klomp et al. 2004). The p.Ile661Thr variant was absent from 289 controls and is reported at a frequency of 0.000158 in the European (non-Finnish) population of the Genome Aggregation Database. Functional studies to determine the effect of the p.Ile661Thr variant in cell lines document overall reduced protein expression compared to wild type (Folmer et al. 2009). Further investigation revealed the p.Ile661Thr variant to result in protein misfolding which was rescued by chemical chaperones such as 4-BPA (van der Velden et al. 2010; van der Woerd et al. 2016). Based on the collective evidence, the p.Ile661Thr variant is classified as pathogenic for familial intrahepatic cholestasis. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population. (less)
|
|
|
Pathogenic
(Feb 04, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
Progressive familial intrahepatic cholestasis
Affected status: unknown
Allele origin:
germline
|
Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Accession: SCV003844340.1
First in ClinVar: Mar 26, 2023 Last updated: Mar 26, 2023 |
Comment:
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 … (more)
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. (less)
|
|
|
Pathogenic
(Mar 24, 2024)
|
criteria provided, single submitter
Method: clinical testing
|
Benign recurrent intrahepatic cholestasis type 1
Affected status: unknown
Allele origin:
unknown
|
Baylor Genetics
Accession: SCV004210707.2
First in ClinVar: Dec 30, 2023 Last updated: Jun 17, 2024 |
|
|
|
Pathogenic
(Jul 01, 2004)
|
no assertion criteria provided
Method: literature only
|
CHOLESTASIS, BENIGN RECURRENT INTRAHEPATIC, 1
Affected status: not provided
Allele origin:
germline
|
OMIM
Accession: SCV000027890.3
First in ClinVar: Apr 04, 2013 Last updated: May 20, 2016 |
Comment on evidence:
In a patient with benign recurrent intrahepatic cholestasis-1 (BRIC1; 243300), Bull et al. (1998) identified a 1982T-C transition in the ATP8B1 gene, resulting in an … (more)
In a patient with benign recurrent intrahepatic cholestasis-1 (BRIC1; 243300), Bull et al. (1998) identified a 1982T-C transition in the ATP8B1 gene, resulting in an ile661-to-thr (I661T) amino acid substitution. The nonconservative mutation was at a site at which all members of the subfamily of P-type ATPases to which ATP8B1 belongs have a leucine or isoleucine residue. The mutation was present on the most common conserved haplotype in BRIC patients of western European descent. It was present in homozygous form in patients from 13 families and in heterozygous form in patients from 6 additional families, and was not found on 84 control chromosomes. Tygstrup et al. (1999) identified homozygosity for the I661T mutation in 5 males with BRIC from the Faroe Islands who were originally reported by Tygstrup and Jensen (1969). Haplotype analysis suggested a founder effect. Klomp et al. (2004) identified the I661T mutation in 14 BRIC families; 3 families were homozygous, 8 were compound heterozygous with another ATP8B1 mutation, and in 3 families a second mutation was not identified. Two families with progressive familial intrahepatic cholestasis (PFIC; 211600) were compound heterozygous for the I661T mutation and another ATP8B1 mutation. In 1 family with BRIC, 4 individuals who were homozygous for the I661T mutation were symptom-free their entire lives, suggesting reduced penetrance. (less)
|
|
|
Pathogenic
(Jul 01, 2004)
|
no assertion criteria provided
Method: literature only
|
CHOLESTASIS, PROGRESSIVE FAMILIAL INTRAHEPATIC, 1
Affected status: not provided
Allele origin:
germline
|
OMIM
Accession: SCV000328232.1
First in ClinVar: Mar 24, 2015 Last updated: Mar 24, 2015 |
Comment on evidence:
In a patient with benign recurrent intrahepatic cholestasis-1 (BRIC1; 243300), Bull et al. (1998) identified a 1982T-C transition in the ATP8B1 gene, resulting in an … (more)
In a patient with benign recurrent intrahepatic cholestasis-1 (BRIC1; 243300), Bull et al. (1998) identified a 1982T-C transition in the ATP8B1 gene, resulting in an ile661-to-thr (I661T) amino acid substitution. The nonconservative mutation was at a site at which all members of the subfamily of P-type ATPases to which ATP8B1 belongs have a leucine or isoleucine residue. The mutation was present on the most common conserved haplotype in BRIC patients of western European descent. It was present in homozygous form in patients from 13 families and in heterozygous form in patients from 6 additional families, and was not found on 84 control chromosomes. Tygstrup et al. (1999) identified homozygosity for the I661T mutation in 5 males with BRIC from the Faroe Islands who were originally reported by Tygstrup and Jensen (1969). Haplotype analysis suggested a founder effect. Klomp et al. (2004) identified the I661T mutation in 14 BRIC families; 3 families were homozygous, 8 were compound heterozygous with another ATP8B1 mutation, and in 3 families a second mutation was not identified. Two families with progressive familial intrahepatic cholestasis (PFIC; 211600) were compound heterozygous for the I661T mutation and another ATP8B1 mutation. In 1 family with BRIC, 4 individuals who were homozygous for the I661T mutation were symptom-free their entire lives, suggesting reduced penetrance. (less)
|
|
|
Pathogenic
(Feb 13, 2024)
|
no assertion criteria provided
Method: clinical testing
|
ATP8B1-related condition
Affected status: unknown
Allele origin:
germline
|
PreventionGenetics, part of Exact Sciences
Accession: SCV004114404.3
First in ClinVar: Nov 20, 2023 Last updated: Oct 08, 2024 |
Comment:
The ATP8B1 c.1982T>C variant is predicted to result in the amino acid substitution p.Ile661Thr. This variant has been reported to be one of the most … (more)
The ATP8B1 c.1982T>C variant is predicted to result in the amino acid substitution p.Ile661Thr. This variant has been reported to be one of the most common causative variants responsible for benign recurrent intrahepatic cholestasis (Bull et al. 1998. PubMed ID: 9500542; Folmer et al. 2009. PubMed ID: 19731236; van der Velden et al. 2010. PubMed ID: 19918981). This variant is reported in 0.016% of alleles in individuals of European (Non-Finnish) descent in gnomAD. This variant is interpreted as pathogenic. (less)
|
|
|
Pathogenic
(-)
|
no assertion criteria provided
Method: clinical testing
|
not provided
Affected status: yes
Allele origin:
germline
|
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen
Study: VKGL Data-share Consensus
Accession: SCV001741583.3 First in ClinVar: Jul 07, 2021 Last updated: Sep 08, 2021 |
|
|
|
Pathogenic
(-)
|
no assertion criteria provided
Method: clinical testing
|
not provided
Affected status: yes
Allele origin:
germline
|
Genome Diagnostics Laboratory, University Medical Center Utrecht
Additional submitter:
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen
Study: VKGL Data-share Consensus
Accession: SCV001929768.1 First in ClinVar: Sep 26, 2021 Last updated: Sep 26, 2021 |
|
|
|
not provided
(-)
|
no classification provided
Method: literature only
|
Progressive familial intrahepatic cholestasis type 1
Affected status: unknown
Allele origin:
germline
|
GeneReviews
Accession: SCV000147884.4
First in ClinVar: Apr 19, 2014 Last updated: Oct 01, 2022 |
Comment:
At least 1 copy of this variant is found in most persons of European descent
|
|
| click to load more click to collapse | |||||
Comment:
Comment:
Across a selection of available literature, the ATP8B1 c.1982T>C (p.Ile661Thr) variant has been reported in a homozygous state in 25 probands, in a compound heterozygous state in eight probands and in a heterozygous state in nine probands (Bull et al. 1998; Tygstrup et al. 1999; Klomp et al. 2004). The clinical presentation of many probands with this variant were described as having benign recurrent intrahepatic cholestatis, but some were described to have progressive disease. This disease has been noted to have reduced penetrance, and five individuals homozygous for the p.Ile661Thr variant were asymptomatic (Klomp et al. 2004). The p.Ile661Thr variant was absent from 289 controls and is reported at a frequency of 0.000158 in the European (non-Finnish) population of the Genome Aggregation Database. Functional studies to determine the effect of the p.Ile661Thr variant in cell lines document overall reduced protein expression compared to wild type (Folmer et al. 2009). Further investigation revealed the p.Ile661Thr variant to result in protein misfolding which was rescued by chemical chaperones such as 4-BPA (van der Velden et al. 2010; van der Woerd et al. 2016). Based on the collective evidence, the p.Ile661Thr variant is classified as pathogenic for familial intrahepatic cholestasis. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population.
Comment:
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.
Comment:
The ATP8B1 c.1982T>C variant is predicted to result in the amino acid substitution p.Ile661Thr. This variant has been reported to be one of the most common causative variants responsible for benign recurrent intrahepatic cholestasis (Bull et al. 1998. PubMed ID: 9500542; Folmer et al. 2009. PubMed ID: 19731236; van der Velden et al. 2010. PubMed ID: 19918981). This variant is reported in 0.016% of alleles in individuals of European (Non-Finnish) descent in gnomAD. This variant is interpreted as pathogenic.
Comment:
At least 1 copy of this variant is found in most persons of European descent
Germline Functional Evidence
| There is no functional evidence in ClinVar for this variation. If you have generated functional data for this variation, please consider submitting that data to ClinVar. |
Comment:
This sequence change replaces isoleucine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 661 of the ATP8B1 protein (p.Ile661Thr). This variant is present in population databases (rs121909100, gnomAD 0.02%). This missense change has been observed in individuals with benign recurrent intrahepatic cholestasis and/or progressive familial intrahepatic cholestasis (PMID: 9500542, 9918928, 15239083, 20232290, 33666275, 34016879). ClinVar contains an entry for this variant (Variation ID: 7267). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt ATP8B1 protein function with a negative predictive value of 80%. Experimental studies have shown that this missense change affects ATP8B1 function (PMID: 19731236, 19918981). For these reasons, this variant has been classified as Pathogenic.
Comment:
Across a selection of available literature, the ATP8B1 c.1982T>C (p.Ile661Thr) variant has been reported in a homozygous state in 25 probands, in a compound heterozygous state in eight probands and in a heterozygous state in nine probands (Bull et al. 1998; Tygstrup et al. 1999; Klomp et al. 2004). The clinical presentation of many probands with this variant were described as having benign recurrent intrahepatic cholestatis, but some were described to have progressive disease. This disease has been noted to have reduced penetrance, and five individuals homozygous for the p.Ile661Thr variant were asymptomatic (Klomp et al. 2004). The p.Ile661Thr variant was absent from 289 controls and is reported at a frequency of 0.000158 in the European (non-Finnish) population of the Genome Aggregation Database. Functional studies to determine the effect of the p.Ile661Thr variant in cell lines document overall reduced protein expression compared to wild type (Folmer et al. 2009). Further investigation revealed the p.Ile661Thr variant to result in protein misfolding which was rescued by chemical chaperones such as 4-BPA (van der Velden et al. 2010; van der Woerd et al. 2016). Based on the collective evidence, the p.Ile661Thr variant is classified as pathogenic for familial intrahepatic cholestasis. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population.
Comment:
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.
Comment:
The ATP8B1 c.1982T>C variant is predicted to result in the amino acid substitution p.Ile661Thr. This variant has been reported to be one of the most common causative variants responsible for benign recurrent intrahepatic cholestasis (Bull et al. 1998. PubMed ID: 9500542; Folmer et al. 2009. PubMed ID: 19731236; van der Velden et al. 2010. PubMed ID: 19918981). This variant is reported in 0.016% of alleles in individuals of European (Non-Finnish) descent in gnomAD. This variant is interpreted as pathogenic.
Comment:
At least 1 copy of this variant is found in most persons of European descent
Citations for germline classification of this variant
Help| Title | Author | Journal | Year | Link |
|---|---|---|---|---|
| Mutation Analysis and Disease Features at Presentation in a Multi-Center Cohort of Children With Monogenic Cholestasis. | Hertel PM | Journal of pediatric gastroenterology and nutrition | 2021 | PMID: 34016879 |
| Impact of Genotype, Serum Bile Acids, and Surgical Biliary Diversion on Native Liver Survival in FIC1 Deficiency. | van Wessel DBE | Hepatology (Baltimore, Md.) | 2021 | PMID: 33666275 |
| ATP8B1 Deficiency. | Adam MP | - | 2021 | PMID: 20301474 |
| Rescue of defective ATP8B1 trafficking by CFTR correctors as a therapeutic strategy for familial intrahepatic cholestasis. | van der Woerd WL | Journal of hepatology | 2016 | PMID: 26879107 |
| ATP8B1 and ABCB11 analysis in 62 children with normal gamma-glutamyl transferase progressive familial intrahepatic cholestasis (PFIC): phenotypic differences between PFIC1 and PFIC2 and natural history. | Davit-Spraul A | Hepatology (Baltimore, Md.) | 2010 | PMID: 20232290 |
| Folding defects in P-type ATP 8B1 associated with hereditary cholestasis are ameliorated by 4-phenylbutyrate. | van der Velden LM | Hepatology (Baltimore, Md.) | 2010 | PMID: 19918981 |
| Differential effects of progressive familial intrahepatic cholestasis type 1 and benign recurrent intrahepatic cholestasis type 1 mutations on canalicular localization of ATP8B1. | Folmer DE | Hepatology (Baltimore, Md.) | 2009 | PMID: 19731236 |
| Characterization of mutations in ATP8B1 associated with hereditary cholestasis. | Klomp LW | Hepatology (Baltimore, Md.) | 2004 | PMID: 15239083 |
| Recurrent familial intrahepatic cholestasis in the Faeroe Islands. Phenotypic heterogeneity but genetic homogeneity. | Tygstrup N | Hepatology (Baltimore, Md.) | 1999 | PMID: 9918928 |
| A gene encoding a P-type ATPase mutated in two forms of hereditary cholestasis. | Bull LN | Nature genetics | 1998 | PMID: 9500542 |
| Intermittent intrahepatic cholestasis of unknown etiology in five young males from the Faroe Islands. | Tygstrup N | Acta medica Scandinavica | 1969 | PMID: 5807632 |
| http://www.egl-eurofins.com/emvclass/emvclass.php?approved_symbol=ATP8B1 | - | - | - | - |
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Text-mined citations for rs121909100 ...
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Record last updated Nov 25, 2024
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