Submissions for variant NM_000443.4(ABCB4):c.1529A>G (p.Asn510Ser)

gnomAD frequency: 0.00009  dbSNP: rs375315619

Total submissions: 13

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Eurofins Ntd Llc (ga)	RCV000427203	SCV000345967	likely pathogenic	not provided	2018-07-17	criteria provided, single submitter	clinical testing
Mendelics	RCV000987913	SCV001137406	pathogenic	Progressive familial intrahepatic cholestasis type 1	2019-05-28	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV000427203	SCV001155111	pathogenic	not provided	2023-12-01	criteria provided, single submitter	clinical testing	ABCB4: PM3:Very Strong, PM2:Supporting, PP4, PS3:Supporting
Baylor Genetics	RCV001003941	SCV001521454	pathogenic	Cholestasis, intrahepatic, of pregnancy, 3	2023-08-12	criteria provided, single submitter	clinical testing
Revvity Omics, Revvity	RCV000427203	SCV002021001	likely pathogenic	not provided	2022-04-08	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV002298568	SCV002598623	likely pathogenic	Progressive familial intrahepatic cholestasis	2023-12-14	criteria provided, single submitter	clinical testing	Variant summary: ABCB4 c.1529A>G (p.Asn510Ser) results in a conservative amino acid change located in the first ATP-binding domain (IPR003439) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.0002 in 251250 control chromosomes, predominantly at a frequency of 0.00062 within the South Asian subpopulation in the gnomAD database, including 1 homozygote. This frequency is not higher than the estimated maximum expected for a pathogenic variant in ABCB4 causing Familial Intrahepatic Cholestasis (0.0022), allowing no conclusion about variant significance. The variant, c.1529A>G, has been reported in the literature in (presumed) compound heterozygous state together with a second (likely) pathogenic variant in individuals affected with hepatobiliary disease and intrahepatic cholestasis of pregnancy (e.g. Delaunay_2016, Stalke_2018, Falcao_2022). The variant has been also reported in (apparent) heterozygosity in affected individuals in whom a second (likely) pathogenic mutation was not identified. These data indicate that the variant is likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function, and demonstrated decreased protein stability (Delaunay_2016). The following publications have been ascertained in the context of this evaluation (PMID: 32917322, 26324191, 26474921, 28587926, 32626542, 28776642, 19467940, 34376370). Eight other submitters have cited clinical-significance assessments for this variant to ClinVar after 2014 and classified the variant with conflicting assessments, i.e. as pathogenic (n=3), likely pathogenic (n=4), or VUS (n=1). Based on the evidence outlined above, the variant was classified as likely pathogenic.
Invitae	RCV000427203	SCV003263803	likely pathogenic	not provided	2024-01-19	criteria provided, single submitter	clinical testing	This sequence change replaces asparagine, which is neutral and polar, with serine, which is neutral and polar, at codon 510 of the ABCB4 protein (p.Asn510Ser). This variant is present in population databases (rs375315619, gnomAD 0.06%), including at least one homozygous and/or hemizygous individual. This missense change has been observed in individuals with autosomal recessive progressive familial intrahepatic cholestasis type 3 and/or intrahepatic cholestasis of pregnancy (PMID: 23022423, 23533021, 26324191, 26474921, 28776642, 32581362, 32917322, 34376370). ClinVar contains an entry for this variant (Variation ID: 291252). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Not Available"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Not Available". The serine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. Studies have shown that this missense change alters ABCB4 gene expression (PMID: 26474921). In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.
Baylor Genetics	RCV003333058	SCV004041259	pathogenic	Progressive familial intrahepatic cholestasis type 3	2023-08-12	criteria provided, single submitter	clinical testing
PreventionGenetics, part of Exact Sciences	RCV004537625	SCV004116808	likely pathogenic	ABCB4-related disorder	2024-02-12	criteria provided, single submitter	clinical testing	The ABCB4 c.1529A>G variant is predicted to result in the amino acid substitution p.Asn510Ser. In the heterozygous state alone, this variant was reported in patients with intrahepatic cholestasis of pregnancy (ICP) (Anzivino. 2013. PubMed ID: 23022423; Poupon. 2013. PubMed ID: 23533021; Falcão. 2021. PubMed ID: 34376370; Stalke 2017. PubMed ID: 28776642). In the compound heterozygous state with another pathogenic ABCB4 variant, this variant was reported to cause progressive familial intrahepatic cholestasis (PFIC) (Delaunay. 2015. PubMed ID: 26474921; Davit-Spraul. 2010. PubMed ID: 20422496; Falcão. 2021. PubMed ID: 34376370). Functional assays in the Delaunay study indicated the p.Asn510Ser change reduced protein stability. This variant is reported in 0.062% of alleles in individuals of South Asian descent in gnomAD. This variant is interpreted as likely pathogenic.
Neuberg Centre For Genomic Medicine, NCGM	RCV003333058	SCV004176544	pathogenic	Progressive familial intrahepatic cholestasis type 3	2023-02-14	criteria provided, single submitter	clinical testing
Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center	RCV003989523	SCV004806278	uncertain significance	Severe early-childhood-onset retinal dystrophy	2024-03-25	criteria provided, single submitter	clinical testing
Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	RCV000427203	SCV000510673	uncertain significance	not provided	2016-10-25	flagged submission	clinical testing	Converted during submission to Uncertain significance.
NIHR Bioresource Rare Diseases, University of Cambridge	RCV001003941	SCV001161915	likely pathogenic	Cholestasis, intrahepatic, of pregnancy, 3		no assertion criteria provided	research