Submissions for variant NM_000443.4(ABCB4):c.449G>A (p.Arg150Lys)

gnomAD frequency: 0.00001  dbSNP: rs757693457

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV004702571	SCV005203931	pathogenic	Progressive familial intrahepatic cholestasis	2024-06-24	criteria provided, single submitter	clinical testing	Variant summary: ABCB4 c.449G>A (p.Arg150Lys) results in a conservative amino acid change located in the ABC transporter type 1, transmembrane domain (ABC transporter type 1, transmembrane domain) of the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 8e-06 in 251350 control chromosomes. c.449G>A has been reported in the literature in heterozygous individuals affected with intrahepatic cholestasis of pregnancy and in a compound heterozygous individual affected with Familial Intrahepatic Cholestasis (Mllenbach_2003, Turro_2020, Nayagam_2022). These data indicate that the variant is very likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 12746424, 35894240, 32581362). ClinVar contains an entry for this variant (Variation ID: 812754). Based on the evidence outlined above, the variant was classified as pathogenic.
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	RCV004789310	SCV005399364	likely pathogenic	Low phospholipid associated cholelithiasis	2023-07-17	criteria provided, single submitter	clinical testing	Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Likely pathogenic. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with intrahepatic cholestasis of pregnancy, 3 (ICP-3; MIM#614972), low phospholipid-associated cholelithiasis (LPAC; MIM# 600803) and progressive familial intrahepatic cholestasis, 3 (PFIC; MIM#602347). (I) 0108 - This gene is associated with both recessive and dominant disease. PFIC is inherited in a recessive manner, whereas ICP-3 and LPAC can be either dominant or recessive. Biallelic variants typically demonstrate less residual protein activity, resulting in earlier onset of the condition with a more severe phenotype (OMIM, PMIDs: 24806754, 32376413). (I) 0200 - Variant is predicted to result in a missense amino acid change from arginine to lysine. (I) 0251 - This variant is heterozygous. (I) 0304 - Variant is present in gnomAD (v2) <0.01 for a recessive condition (2 heterozygotes, 0 homozygotes). (SP) 0502 - Missense variant with conflicting in silico predictions and high conservation. (I) 0600 - Variant is located in the annotated ABC transporter transmembrane domain (DECIPHER) . (I) 0705 - No comparable missense variants have previous evidence for pathogenicity. (I) 0802 - This variant has moderate previous evidence of pathogenicity in unrelated individuals. This variant has been observed as heterozygous in one family and one unrelated individual with intrahepatic cholestasis of pregnancy (PMID: 12746424). This variant has also been observed with a canonical splice variant, c.834-1G>A, in a large rare disease cohort study; however, it is unclear if these two variants were in cis or in trans (PMID: 32581362). (SP) 0902 - This variant has moderate evidence for segregation with disease. This variant has been observed as heterozygous in one asymptomatic male and three females with intrahepatic cholestasis of pregnancy in one family (PMID: 12746424, 32581362). (SP) 1010 - Functional evidence for this variant is inconclusive. Functional studies using flow cytometry on a glycoprotein mutated with this variant show no difference in activity to wild type (PMID: 12746424). However, this variant could have a different effect on the protein that is not tested by this assay. (I) 1206 - This variant has been shown to be paternally inherited and to be in cis with NM_000443.3(ABCB4):c.834-1G>A. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign
Fulgent Genetics, Fulgent Genetics	RCV005047190	SCV005674295	likely pathogenic	Progressive familial intrahepatic cholestasis type 3; Low phospholipid associated cholelithiasis; Cholestasis, intrahepatic, of pregnancy, 3	2024-06-25	criteria provided, single submitter	clinical testing
NIHR Bioresource Rare Diseases, University of Cambridge	RCV001003564	SCV001161925	likely pathogenic	Cholestasis, intrahepatic, of pregnancy, 3		no assertion criteria provided	research