Submissions for variant NM_000443.4(ABCB4):c.2137G>A (p.Val713Met)

gnomAD frequency: 0.00019  dbSNP: rs373122168

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Illumina Laboratory Services, Illumina	RCV000359312	SCV000470135	uncertain significance	Cholestasis, intrahepatic, of pregnancy, 3	2018-01-12	criteria provided, single submitter	clinical testing	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease.
Illumina Laboratory Services, Illumina	RCV000267319	SCV000470136	uncertain significance	Progressive familial intrahepatic cholestasis type 3	2018-01-12	criteria provided, single submitter	clinical testing	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease.
Eurofins Ntd Llc (ga)	RCV000733560	SCV000861639	uncertain significance	not provided	2018-06-05	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV002265747	SCV002548018	uncertain significance	not specified	2024-10-14	criteria provided, single submitter	clinical testing	Variant summary: ABCB4 c.2137G>A (p.Val713Met) results in a conservative amino acid change located in the 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 0.00011 in 251050 control chromosomes in the gnomAD database, including 1 homozygotes. This frequency is not significantly higher than estimated for a pathogenic variant in ABCB4 causing Familial Intrahepatic Cholestasis (0.00011 vs 0.0022), allowing no conclusion about variant significance. c.2137G>A has been reported in the literature in individuals affected with Familial Intrahepatic Cholestasis in heterozygous state (example: Wu_2020, Hegarty_2024). These report(s) do not provide unequivocal conclusions about association of the variant with Familial Intrahepatic Cholestasis. 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: 32321542, 38374565). ClinVar contains an entry for this variant (Variation ID: 360794). Based on the evidence outlined above, the variant was classified as uncertain significance.
PreventionGenetics, part of Exact Sciences	RCV004757222	SCV005347030	uncertain significance	ABCB4-related disorder	2024-08-16	no assertion criteria provided	clinical testing	The ABCB4 c.2137G>A variant is predicted to result in the amino acid substitution p.Val713Met. This variant was reported in with a second ABCB4 variant in an individual with progressive familial intrahepatic cholestasis (Wu et al 2020. PubMed ID: 32321542). This variant was also observed in a large cohort study of individuals with intrahepatic cholestasis of pregnancy (Supp. Table 1 Liu X et al 2022. PubMed ID: 36046230). This variant is reported in 0.030% of alleles in individuals of East Asian descent in gnomAD, including one homozygote. At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.