Submissions for variant NM_001374385.1(ATP8B1):c.2546G>A (p.Arg849Gln)

gnomAD frequency: 0.00002  dbSNP: rs144656719

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000727533	SCV000523642	uncertain significance	not provided	2016-11-16	criteria provided, single submitter	clinical testing	The R849Q variant has not been published as a pathogenic variant, nor has it been reported as a benign variant to our knowledge. The R849Q variant was not observed at any significant frequency in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project. The R849Q variant has been observed as homozygous in a single unaffected individual sent for whole exome sequence analysis at GeneDx. The R849Q variant is a semi-conservative amino acid substitution, which may impact secondary protein structure as these residues differ in some properties. This substitution occurs at a position that is not conserved, and in silico analysis predicts this variant likely does not alter the protein structure/function. In summary, based on the currently available information, it is unclear whether this variant is a pathogenic variant or a rare benign variant.
Eurofins Ntd Llc (ga)	RCV000727533	SCV000709504	uncertain significance	not provided	2018-07-24	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV000764165	SCV000895167	uncertain significance	Progressive familial intrahepatic cholestasis type 1; Cholestasis, intrahepatic, of pregnancy, 1; Benign recurrent intrahepatic cholestasis type 1	2018-10-31	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV001122546	SCV001281270	uncertain significance	Progressive familial intrahepatic cholestasis type 1	2017-05-28	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	RCV001330098	SCV001521698	uncertain significance	Benign recurrent intrahepatic cholestasis type 1	2019-09-06	criteria provided, single submitter	clinical testing	This variant was determined to be of uncertain significance according to ACMG Guidelines, 2015 [PMID:25741868].
Invitae	RCV000727533	SCV003291359	uncertain significance	not provided	2022-05-19	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 849 of the ATP8B1 protein (p.Arg849Gln). This variant is present in population databases (rs144656719, gnomAD 0.02%). This missense change has been observed in individual(s) with intrahepatic cholestasis (PMID: 26126923). ClinVar contains an entry for this variant (Variation ID: 383293). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Tolerated"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0". The glutamine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.