Submissions for variant NM_000443.4(ABCB4):c.2784-12T>C

gnomAD frequency: 0.00019  dbSNP: rs201498350

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Mendelics	RCV000987906	SCV001137399	likely pathogenic	Progressive familial intrahepatic cholestasis type 1	2020-03-06	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV002282417	SCV002572221	likely pathogenic	Progressive familial intrahepatic cholestasis	2022-08-22	criteria provided, single submitter	clinical testing	Variant summary: ABCB4 c.2784-12T>C alters a non-conserved nucleotide located close to a canonical splice site and therefore could affect mRNA splicing, leading to a significantly altered protein sequence. Three computational tools predict the variant has no significant impact on splicing and one predicts the variant weakens a canonical 3' acceptor site. At least one publication reports experimental evidence that this variant affects mRNA splicing. The study found that wild-type transcripts are spliced into mRNA with and without exon 23 and introduction of the variant led to increased exon skipping, resulting in a greater proportion of mRNA transcripts lacking exon 23 (e.g. Belbin_2021). The variant allele was found at a frequency of 2e-05 in 250744 control chromosomes (gnomAD). c.2784-12T>C has been reported in the literature in four homozygous individuals affected with liver cirrhosis, and in one unaffected homozygous individual (e.g. Belbin_2021). This report does not provide unequivocal conclusions about association of the variant with Familial Intrahepatic Cholestasis. 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 likely pathogenic. Based on the evidence outlined above, the variant was classified as likely pathogenic.
GeneDx	RCV002286794	SCV002577287	pathogenic	not provided	2022-09-30	criteria provided, single submitter	clinical testing	Published functional studies demonstrate a damaging effect due to aberrant splicing that results in the skipping of in-frame exon 23 (Belbin GM et al., 2021); Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 35905201, 34678161)
Invitae	RCV002286794	SCV003029428	uncertain significance	not provided	2022-08-13	criteria provided, single submitter	clinical testing	This sequence change falls in intron 22 of the ABCB4 gene. It does not directly change the encoded amino acid sequence of the ABCB4 protein. This variant is present in population databases (rs201498350, gnomAD 0.006%). This variant has not been reported in the literature in individuals affected with ABCB4-related conditions. ClinVar contains an entry for this variant (Variation ID: 802326). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Mayo Clinic Laboratories, Mayo Clinic	RCV002286794	SCV004224024	uncertain significance	not provided	2023-02-10	criteria provided, single submitter	clinical testing	PM2
Illumina Laboratory Services, Illumina	RCV003985096	SCV004801605	uncertain significance	ABCB4-Related Intrahepatic Cholestasis	2021-06-08	criteria provided, single submitter	clinical testing	The ABCB4 c.2784-12T>C variant occurs in a splice region. This variant was identified in a homozygous state in four individuals with a phenotype consistent with advanced liver disease and in one individual with liver steatosis on imaging. Heterozygous carriers of the variant were also found to experience an increased risk of liver disease. In vitro analyses confirmed the variant results in skipping of exon 23 (Belbin et al. 2021). The c.2784-12T>C variant is reported at a frequency of 0.000633 in the Admixed American population of the Genome Aggregation Database (version 4.0.0) including one homozygote. Belbin et al. noted a high frequency of the variant in the Puerto Rican population and speculated it resulted from a founder effect (Belbin et al. 2021). Based on the available evidence, the c.2784-12T>C variant is classified as a variant of uncertain significance for ABCB4-related intrahepatic cholestasis.