NM_001374385.1(ATP8B1):c.2854C>T (p.Arg952Ter) AND not provided

Germline classification:: Pathogenic (5 submissions)
Last evaluated:: Dec 9, 2023
Review status:: 2 stars out of maximum of 4 stars
criteria provided, multiple submitters, no conflicts

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:: RCV000730680.23

Allele description [Variation Report for NM_001374385.1(ATP8B1):c.2854C>T (p.Arg952Ter)]

NM_001374385.1(ATP8B1):c.2854C>T (p.Arg952Ter)

Genes:

ATP8B1-AS1:ATP8B1 antisense RNA 1 [Gene - HGNC]
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.2854C>T (p.Arg952Ter)

HGVS:

NC_000018.10:g.57655271G>A
NG_007148.3:g.153552C>T
NM_001374385.1:c.2854C>TMANE SELECT
NM_001374386.1:c.2704C>T
NM_005603.6:c.2854C>T
NP_001361314.1:p.Arg952Ter
NP_001361315.1:p.Arg902Ter
NP_005594.2:p.Arg952Ter
LRG_1205t1:c.2854C>T
LRG_1205:g.153552C>T
LRG_1205p1:p.Arg952Ter
NC_000018.9:g.55322503G>A
NM_005603.4:c.2854C>T

Protein change:

R902*

Links:

dbSNP: rs765889649

NCBI 1000 Genomes Browser:

rs765889649

Molecular consequence:

NM_001374385.1:c.2854C>T - nonsense - [Sequence Ontology: SO:0001587]
NM_001374386.1:c.2704C>T - nonsense - [Sequence Ontology: SO:0001587]
NM_005603.6:c.2854C>T - nonsense - [Sequence Ontology: SO:0001587]

Observations:

Condition(s)

Synonyms:: none provided
Identifiers:: MedGen: C3661900

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000858434	Eurofins Ntd Llc (ga)	criteria provided, single submitter (EGL Classification Definitions 2015)	Pathogenic (Nov 29, 2017)	germline	clinical testing	Citation Link,
SCV001247823	CeGaT Center for Human Genetics Tuebingen	criteria provided, single submitter (CeGaT Center For Human Genetics Tuebingen Variant Classification Criteria Version 2)	Pathogenic (Oct 1, 2016)	germline	clinical testing	Citation Link,
SCV001424909	GeneDx	criteria provided, single submitter (GeneDx Variant Classification (06012015))	Pathogenic (Jun 11, 2020)	germline	clinical testing	Citation Link,
SCV001551476	Department of Pathology and Laboratory Medicine, Sinai Health System - The Canadian Open Genetics Repository (COGR) See additional submitters Franklin by Genoox	no assertion criteria provided	Pathogenic	unknown	clinical testing
SCV004297589	Invitae	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Dec 9, 2023)	germline	clinical testing	PubMed (4) [See all records that cite these PMIDs] 15239083, 22525741, 33666275, 28492532

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	yes	1	not provided	not provided	not provided	not provided	clinical testing
not provided	unknown	yes	not provided	not provided	not provided	not provided	not provided	clinical testing
not provided	germline	unknown	1	not provided	not provided	not provided	not provided	clinical 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

Characterization of urinary bile acids in a pediatric BRIC-1 patient: effect of rifampicin treatment.

Mizuochi T, Kimura A, Tanaka A, Muto A, Nittono H, Seki Y, Takahashi T, Kurosawa T, Kage M, Takikawa H, Matsuishi T.

Clin Chim Acta. 2012 Aug 16;413(15-16):1301-4. doi: 10.1016/j.cca.2012.04.011. Epub 2012 Apr 14.

PubMed [citation]

PMID:: 22525741

See all PubMed Citations (4)

Details of each submission

From Eurofins Ntd Llc (ga), SCV000858434.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	1	not provided	not provided	clinical testing	not provided

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		1	not provided	not provided	not provided

From CeGaT Center for Human Genetics Tuebingen, SCV001247823.20

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	1	not provided	not provided	clinical testing	not provided

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	yes	not provided	not provided	not provided		1	not provided	not provided	not provided

From GeneDx, SCV001424909.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1		not provided	not provided	not provided	clinical testing	not provided

Description

Identified in homozygous state due to UPD or in compound heterozygous state with other ATP8B1 variants in multiple families with hereditary cholestasis referred for genetic testing at GeneDx or in published literature (Klomp et al., 2004). Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease. Observed in 3/282880 (0.0011%) alleles in large population cohorts, and no individuals were reported to be homozygous (Lek et al., 2016). We interpret R952X as a pathogenic variant.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	yes	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Department of Pathology and Laboratory Medicine, Sinai Health System - The Canadian Open Genetics Repository (COGR), SCV001551476.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	not provided

Description

The ATP8B1 p.Arg952* variant was identified in 4 of 398 proband chromosomes (frequency: 0.01005) from individuals or families with progressive familial intrahepatic cholestasis (PFIC) or benign recurrent intrahepatic cholestasis (BRIC) (Liu_2010_PMID:20038848; Klomp_2004_PMID:15239083). The variant was also identified in dbSNP (ID: rs765889649), ClinVar (classified as pathogenic by EGL Genetic Diagnostics) and Cosmic (FATHMM prediction: pathogenic; score=0.96). The variant was identified in control databases in 3 of 282880 chromosomes at a frequency of 0.000011 (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: African in 2 of 24970 chromosomes (freq: 0.00008) and European (non-Finnish) in 1 of 129180 chromosomes (freq: 0.000008), while the variant was not observed in the Latino, Ashkenazi Jewish, East Asian, European (Finnish), Other or South Asian populations. The c.2854C>T variant leads to a premature stop codon at position 952 which is predicted to lead to a truncated or absent protein and loss of function. Loss of function variants of the ATP8B1 gene are an established mechanism of disease in PFIC and BRIC and, in the homozygous or compound heterozygous state, is the type of variant expected to cause these disorders. In summary, based on the above information this variant meets our laboratoryâ€šÃ„Ã´s criteria to be classified as pathogenic.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	unknown	yes	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Invitae, SCV004297589.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (4)

Description

This sequence change creates a premature translational stop signal (p.Arg952*) in the ATP8B1 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in ATP8B1 are known to be pathogenic (PMID: 15239083, 22525741). This variant is present in population databases (rs765889649, gnomAD 0.008%). This premature translational stop signal has been observed in individual(s) with familial intrahepatic cholestasis type 1 deficiency (PMID: 33666275). ClinVar contains an entry for this variant (Variation ID: 595193). For these reasons, this variant has been classified as Pathogenic.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

Last Updated: Apr 15, 2024

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