rs121909100

chr18-57669433-A-G

Variant summary

Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PP2 PP3_Moderate PP5_Very_Strong

The NM_001374385.1(ATP8B1):c.1982T>C(p.Ile661Thr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000159 in 1,613,520 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. I661V) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.000099 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00017 (0 hom.)
• Consequence: ATP8B1 NM_001374385.1 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:14 O:1
• Conservation: PhyloP100: 9.32

Genes affected

ATP8B1 (HGNC:3706): (ATPase phospholipid transporting 8B1) This gene encodes a member of the P-type cation transport ATPase family, which belongs to the subfamily of aminophospholipid-transporting ATPases. The aminophospholipid translocases transport phosphatidylserine and phosphatidylethanolamine from one side of a bilayer to another. Mutations in this gene may result in progressive familial intrahepatic cholestasis type 1 and in benign recurrent intrahepatic cholestasis. [provided by RefSeq, Jul 2008]

(HGNC:):

ACMG classification

Verdict is Pathogenic. Variant got 11 ACMG points.

• PP2: Missense variant where missense usually causes diseases, ATP8B1
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.922
• PP5: Variant 18-57669433-A-G is Pathogenic according to our data. Variant chr18-57669433-A-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 7267.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr18-57669433-A-G is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ATP8B1	NM_001374385.1	c.1982T>C	p.Ile661Thr	missense_variant	18/28	ENST00000648908.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ATP8B1	ENST00000648908.2	c.1982T>C	p.Ile661Thr	missense_variant	18/28		NM_001374385.1	P1
	ENST00000588925.5	n.570+27381A>G		intron_variant, non_coding_transcript_variant		2

Frequencies

GnomAD3 genomes AF: 0.0000986 AC: 15 AN: 152130 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000206

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000956 AC: 24 AN: 251022 Hom.: 0 AF XY: 0.000111 AC XY: 15 AN XY: 135726

Gnomad AFR exome AF: 0.0000616

Gnomad AMR exome AF: 0.0000580

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000109

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000167

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000166 AC: 242 AN: 1461390 Hom.: 0 Cov.: 30 AF XY: 0.000176 AC XY: 128 AN XY: 727018

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000447

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000504

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.0000375

Gnomad4 NFE exome AF: 0.000206

Gnomad4 OTH exome AF: 0.000116

GnomAD4 genome AF: 0.0000986 AC: 15 AN: 152130 Hom.: 0 Cov.: 33 AF XY: 0.0000673 AC XY: 5 AN XY: 74324

Gnomad4 AFR AF: 0.0000241

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000206

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000162 Hom.: 0

Bravo AF: 0.000102

TwinsUK AF: 0.000539 AC: 2

ALSPAC AF: 0.000519 AC: 2

ESP6500AA AF: 0.000227 AC: 1

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.0000906 AC: 11

EpiCase AF: 0.000109

EpiControl AF: 0.000178

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:14 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:6

Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Dec 25, 2023	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. -
Pathogenic, criteria provided, single submitter	clinical testing	Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	Feb 06, 2024	- -
Pathogenic, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Pathogenic, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jun 03, 2016	- -
Pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Jul 03, 2019	- -

Progressive familial intrahepatic cholestasis type 1 Pathogenic:3 Other:1

Pathogenic, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Oct 16, 2018	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. -
Pathogenic, no assertion criteria provided	literature only	OMIM	Jul 01, 2004	- -
not provided, no classification provided	literature only	GeneReviews	-	At least 1 copy of this variant is found in most persons of European descent -
Likely pathogenic, criteria provided, single submitter	clinical testing	Mendelics	Jun 19, 2023	- -

Benign recurrent intrahepatic cholestasis type 1 Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Oct 04, 2023	- -
Pathogenic, no assertion criteria provided	literature only	OMIM	Jul 01, 2004	- -
Pathogenic, criteria provided, single submitter	clinical testing	MGZ Medical Genetics Center	May 13, 2022	- -

Progressive familial intrahepatic cholestasis Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

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

Feb 04, 2023

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. -

ATP8B1-related condition Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Feb 13, 2024

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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.48
BayesDel_addAF	Pathogenic	0.24	D
BayesDel_noAF	Pathogenic	0.37
Cadd	Pathogenic	27
Dann	Uncertain	1.0
DEOGEN2	Uncertain	0.50	D;D
Eigen	Pathogenic	1.0
Eigen_PC	Pathogenic	0.95
FATHMM_MKL	Pathogenic	0.99	D
M_CAP	Uncertain	0.28	D
MetaRNN	Pathogenic	0.92	D;D
MetaSVM	Pathogenic	0.79	D
MutationAssessor	Pathogenic	3.4	M;M
MutationTaster	Benign	1.0	A;A
PrimateAI	Uncertain	0.57	T
PROVEAN	Uncertain	-3.2	D;.
REVEL	Pathogenic	0.92
Sift	Uncertain	0.0020	D;.
Sift4G	Uncertain	0.0030	D;.
Polyphen		1.0	D;D
Vest4		0.90
MVP		0.94
ClinPred		0.73	D
GERP RS		5.8
Varity_R		0.54
gMVP		0.92

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs121909100; hg19: chr18-55336665;