ClinVar Miner

Submissions for variant NM_001374385.1(ATP8B1):c.1982T>C (p.Ile661Thr) (rs121909100)

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Total submissions: 9
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Eurofins NTD, LLC RCV000723736 SCV000331489 pathogenic not provided 2016-06-03 criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,Illumina RCV000007690 SCV000914821 pathogenic Cholestasis, progressive familial intrahepatic 1 2018-10-16 criteria provided, single submitter clinical testing 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.
Mendelics RCV000007690 SCV001140912 benign Cholestasis, progressive familial intrahepatic 1 2019-05-28 criteria provided, single submitter clinical testing
OMIM RCV000007689 SCV000027890 pathogenic Cholestasis, benign recurrent intrahepatic 1 2004-07-01 no assertion criteria provided literature only
GeneReviews RCV000007690 SCV000147884 pathogenic Cholestasis, progressive familial intrahepatic 1 2021-09-01 no assertion criteria provided literature only At least 1 copy of this variant is found in most persons of European descent
OMIM RCV000007690 SCV000328232 pathogenic Cholestasis, progressive familial intrahepatic 1 2004-07-01 no assertion criteria provided literature only
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen RCV000723736 SCV001741583 pathogenic not provided no assertion criteria provided clinical testing
Genome Diagnostics Laboratory, University Medical Center Utrecht RCV000723736 SCV001929768 pathogenic not provided no assertion criteria provided clinical testing
PerkinElmer Genomics RCV000723736 SCV002022083 pathogenic not provided 2019-07-03 no assertion criteria provided clinical testing

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