Submissions for variant NM_000443.4(ABCB4):c.602C>T (p.Thr201Met)

gnomAD frequency: 0.00001  dbSNP: rs753318087

Total submissions: 3

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Eurofins Ntd Llc (ga)	RCV000595281	SCV000701720	uncertain significance	not provided	2016-09-27	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV002282252	SCV002572352	uncertain significance	not specified	2022-08-26	criteria provided, single submitter	clinical testing	Variant summary: ABCB4 c.602C>T (p.Thr201Met) results in a non-conservative amino acid change located in the first transmembrane domain (IPR011527) 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 251368 control chromosomes (gnomAD). c.602C>T has been reported in the literature in an individual affected with Familial Intrahepatic Cholestasis (GordoGilart_2015), who also carried a second missense variant (E1118K). Authors of this study also reported experimental evidence evaluating the impact on protein function for both missense changes, and demonstrated that the T201M variant reduced expression and also decreased phosphatidylcholine efflux activity, resulting in about 27% residual function compared to the WT (GordoGilart_2015), while the other missense (E1118K) didn't affect expression, but caused a partial reduction in function (resulting in ~39% residual function). These findings were in accordance with the milder phenotype of the reported patient (GordoGilart_2015). 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.
PreventionGenetics, part of Exact Sciences	RCV004530657	SCV004716845	uncertain significance	ABCB4-related disorder	2024-01-17	criteria provided, single submitter	clinical testing	The ABCB4 c.602C>T variant is predicted to result in the amino acid substitution p.Thr201Met. This variant, along with another ABCB4 missense variant, has been reported in an individual with progressive familial intrahepatic cholestasis type 3 (Table 2, Gordo-Gilart et al 2015. PubMed ID: 24594635). In vitro functional studies suggest this variant results in reduced protein expression and activity compared to control (Gordo-Gilart et al 2015. PubMed ID: 24594635). This variant is reported in 0.0062% of alleles in individuals of African descent in gnomAD. Although we suspect that this variant may be pathogenic, at this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.