Submissions for variant NM_000443.4(ABCB4):c.1637C>A (p.Ala546Asp)

dbSNP: rs121918441

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Eurofins Ntd Llc (ga)	RCV000728477	SCV000856056	uncertain significance	not provided	2018-07-30	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV002509158	SCV002819689	uncertain significance	not specified	2022-12-20	criteria provided, single submitter	clinical testing	Variant summary: ABCB4 c.1637C>A (p.Ala546Asp) results in a non-conservative amino acid change located in the ABC transporter-like, ATP-binding domain (IPR003439) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 4e-06 in 251282 control chromosomes. c.1637C>A has been reported in the literature as a heterozygous genotype (second allele not specified) in one individual with Intrahepatic Cholestasis of Pregnancy (example Dixon_2000) who has been cited by others and as a presumed compound heterozygous genotype (phase not specified) in at-least one individual with Progressive familial intrahepatic cholestasis type 3 (PFIC3) (example, Sticova_2020 cited in Hertel_2021). These data do not allow any conclusion about variant significance. At least one publication reports experimental evidence evaluating an impact on protein function (example Dixon_2000). The most pronounced variant effect results in reduced cell surface expression, abnormal protein glycosylation and abnormal trafficking of the mutant to plasma membrane, but not its activity. One clinical diagnostic laboratory has submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation and classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as VUS-possibly pathogenic.
OMIM	RCV000014687	SCV000034942	pathogenic	Cholestasis, intrahepatic, of pregnancy, 3	2000-05-01	no assertion criteria provided	literature only
PreventionGenetics, part of Exact Sciences	RCV004532349	SCV004717607	uncertain significance	ABCB4-related disorder	2024-04-10	no assertion criteria provided	clinical testing	The ABCB4 c.1637C>A variant is predicted to result in the amino acid substitution p.Ala546Asp. This variant has been reported in the heterozygous state in a patient with intrahepatic cholestasis of pregnancy (Dixon et al. 2000. PubMed ID: 10767346). Functional studies indicate the p.Ala546Asp variant disrupts protein trafficking, resulting in a lack of functional protein at the cell surface (Dixon et al. 2000. PubMed ID: 10767346). This variant was also seen as compound heterozygous in one individual from a study of children with monogenic cholestasis (Hertel et al. 2021. PubMed ID: 34016879). This variant is reported in 0.00088% of alleles in individuals of European (Non-Finnish) descent in gnomAD. At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.