Submissions for variant NM_001374385.1(ATP8B1):c.913T>A (p.Phe305Ile)

gnomAD frequency: 0.00120  dbSNP: rs150860808

Total submissions: 10

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Eurofins Ntd Llc (ga)	RCV000263650	SCV000343937	likely benign	not specified	2016-07-15	criteria provided, single submitter	clinical testing
GeneDx	RCV000766301	SCV000524097	uncertain significance	not provided	2024-03-21	criteria provided, single submitter	clinical testing	In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Identified in the heterozygous state in individuals with intrahepatic cholestasis of pregnancy, chronic pancreatitis, or cryptogenic cholestasis in whom a second variant in ATP8B1 was not identified. This variant was also identified in multiple healthy control individuals (PMID: 15888793, 24260417, 29238877); This variant is associated with the following publications: (PMID: Barkaoui[Article]2018, 33666275, 24260417, 29238877, 28733223, 34679599, 15888793)
CeGaT Center for Human Genetics Tuebingen	RCV000766301	SCV001151552	uncertain significance	not provided	2016-06-01	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV001122637	SCV001281377	uncertain significance	Progressive familial intrahepatic cholestasis type 1	2017-04-27	criteria provided, single submitter	clinical testing	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000263650	SCV002103783	uncertain significance	not specified	2022-02-18	criteria provided, single submitter	clinical testing	Variant summary: ATP8B1 c.913T>A (p.Phe305Ile) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.0012 in 251422 control chromosomes. This frequency is not significantly higher than expected for a pathogenic variant in ATP8B1 causing Familial Intrahepatic Cholestasis (0.0012 vs 0.0022), allowing no conclusion about variant significance. c.913T>A has been reported in the literature in individuals affected with intrahepatic cholestasis of pregnancy (Mullenbach_2005) or FIC1 deficiency (van Wessel_2021). These reports do not provide unequivocal conclusions about association of the variant with Familial Intrahepatic Cholestasis. Four clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation (likely benign n=1, VUS n=3). Based on the evidence outlined above, the variant was classified as uncertain significance.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000766301	SCV002245259	benign	not provided	2024-01-31	criteria provided, single submitter	clinical testing
Mayo Clinic Laboratories, Mayo Clinic	RCV000766301	SCV005408619	uncertain significance	not provided	2024-07-02	criteria provided, single submitter	clinical testing	BS1
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	RCV000766301	SCV001744356	likely benign	not provided		no assertion criteria provided	clinical testing
Genome Diagnostics Laboratory, University Medical Center Utrecht	RCV000766301	SCV001930199	likely benign	not provided		no assertion criteria provided	clinical testing
PreventionGenetics, part of Exact Sciences	RCV004549616	SCV004747852	uncertain significance	ATP8B1-related disorder	2024-05-08	no assertion criteria provided	clinical testing	The ATP8B1 c.913T>A variant is predicted to result in the amino acid substitution p.Phe305Ile. This variant has been reported in patients with ATP8B1-related disease, including PFIC, cryptogenic cholestasis, intrahepatic cholestasis of pregnancy, and chronic pancreatitis (Müllenbach et al. 2005. PubMed ID: 15888793; van der Woerd et al. 2013. PubMed ID: 24260417; Dröge et al. 2017. PubMed ID: 28733223; Vitale et al. 2018. PubMed ID: 29238877). However, this variant has also been documented in healthy controls (Müllenbach et al. 2005. PubMed ID: 15888793; Woerd et al. 2013. PubMed ID: 24260417). This variant is found at an allele frequency of up to 0.42% in individuals of Ashkenazi Jewish descent in gnomAD. Additionally, in gnomAD v4 (available only on GRCh38), this variant is reported in 0.36% of individuals of Ashkenazi Jewish descent, including 8 homozygotes that were identified mostly in individuals of European descent. This population data is not consistent with this variant being a primary cause of disease. At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.