Submissions for variant NM_005603.6(ATP8B1):c.208G>A (p.Asp70Asn) (rs34719006)

Total submissions: 12

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
EGL Genetic Diagnostics, Eurofins Clinical Diagnostics	RCV000177233	SCV000229075	likely benign	not specified	2017-04-26	criteria provided, single submitter	clinical testing
GeneDx	RCV000952767	SCV000577533	benign	not provided	2018-06-01	criteria provided, single submitter	clinical testing	This variant is associated with the following publications: (PMID: 15888793, 4260417, 28733223, 19731236, 20981092, 15239083, 22995991, 24627769, 24260417, 27884173, 23891399, 32917322)
Genomic Research Center,Shahid Beheshti University of Medical Sciences	RCV000007694	SCV000784325	uncertain significance	Cholestasis, intrahepatic, of pregnancy, 1	2018-03-05	criteria provided, single submitter	clinical testing
Genomic Research Center,Shahid Beheshti University of Medical Sciences	RCV000661994	SCV000784326	uncertain significance	Cholestasis, benign recurrent intrahepatic 1	2018-03-05	criteria provided, single submitter	clinical testing
Genomic Research Center,Shahid Beheshti University of Medical Sciences	RCV000661995	SCV000784327	uncertain significance	Progressive familial intrahepatic cholestasis 2	2018-03-05	criteria provided, single submitter	clinical testing
Genomic Research Center,Shahid Beheshti University of Medical Sciences	RCV000661996	SCV000784328	uncertain significance	Cholestasis, progressive familial intrahepatic 1	2018-03-05	criteria provided, single submitter	clinical testing
Invitae	RCV000952767	SCV001099294	likely benign	not provided	2019-12-31	criteria provided, single submitter	clinical testing
Mendelics	RCV000661996	SCV001140913	uncertain significance	Cholestasis, progressive familial intrahepatic 1	2019-05-28	criteria provided, single submitter	clinical testing
Illumina Clinical Services Laboratory,Illumina	RCV000661996	SCV001285582	uncertain significance	Cholestasis, progressive familial intrahepatic 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.
Baylor Genetics	RCV000661994	SCV001528420	uncertain significance	Cholestasis, benign recurrent intrahepatic 1	2018-07-30	criteria provided, single submitter	clinical testing	This variant was determined to be of uncertain significance according to ACMG Guidelines, 2015 [PMID:25741868].
OMIM	RCV000007694	SCV000027895	pathogenic	Cholestasis, intrahepatic, of pregnancy, 1	2005-06-01	no assertion criteria provided	literature only
Department of Pathology and Laboratory Medicine,Sinai Health System	RCV000952767	SCV001549529	likely benign	not provided		no assertion criteria provided	clinical testing	The ATP8B1 p.D70N variant was identified in the literature in 8 heterozygous individuals with chronic pancreatitis, 3 heterozygous individuals with intrahepatic cholestasis of pregnancy, two compound heterozygous individuals with benign recurrent intrahepatic cholestasis, a heterozygous individual with ‘low-normal’ gamma glutamyl transpeptidase (gGT) cholestasis and two heterozygous individuals with liver injury; this variant was also reported as a heterozygous variant in 9 healthy controls (Mullenbach_2005_PMID:15888793; Klomp_2004_PMID:15239083; Van der Woerd_2013_PMID:24260417; McKay_2013_PMID:24627769; Giovannoni_2015_PMID:26678486; Stolz_2019_PMID:30934130). The variant was identified in dbSNP (ID: rs34719006) and ClinVar (classified as uncertain significance by GeneDx, Illumina, Mendelics and Genomic Research Centre, Shihad Beheshti University of Medical Sciences; as likely benign by EGL Genetic Diagnostics and Invitae; and as pathogenic by OMIM). The variant was identified in control databases in 877 of 282502 chromosomes (2 homozygous) at a frequency of 0.003104, and was observed at the highest frequency in the European (non-Finnish) population in 567 of 129006 chromosomes (freq: 0.004395) (Genome Aggregation Database March 6, 2019, v2.1.1). The p.D70 residue is conserved in mammals however computational analyses (MUT Assesor, PolyPhen-2, SIFT, MutationTaster, Revel, FATHMM, MetaLR, DANN) do not suggest a high likelihood of impact to the protein; this information is not very predictive of pathogenicity. In vitro functional analysis reveals that the p.D70N variant does not affect protein localization and has residual activity compared to wildtype (Folmer_2009_PMID:19731236; Takatsu_2014_PMID:25315773). The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (Splice AI exome) do not predict a difference in splicing. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time although we would lean towards a more benign role for this variant. This variant is classified as likely benign.