ClinVar Miner

Submissions for variant NM_000392.5(ABCC2):c.3517A>T (p.Ile1173Phe)

gnomAD frequency: 0.00001  dbSNP: rs72558201
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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Illumina Laboratory Services, Illumina RCV000008929 SCV000359803 pathogenic Dubin-Johnson syndrome 2017-04-27 criteria provided, single submitter clinical testing The ABCC2 c.3517A>T (p.Ile1173Phe) missense variant has been reported in a single study in which it was found in a total of 24 individuals with Dubin-Johnson syndrome, including in a homozygous state in 22 patients of Iranian Jewish origin and in a compound heterozygous state in two patients of mixed Iranian Jewish and Moroccan Jewish origin (Mor-Cohen et al. 2001). The p.Ile1173Phe variant was also detected in a heterozygous state in 14 of 243 healthy Iranian Jewish controls and is reported at a frequency of 0.00003 in the European (non-Finnish) population of the Exome Aggregation Consortium. This frequency is based on two alleles in a region of good sequence coverage so the variant is presumed to be rare. Expression studies indicated that the p.Ile1173Phe variant resulted in impaired transport activity of the ABCC2 protein, expression of the variant protein was low, and the variant protein itself mislocated to the endoplasmic reticulum (Mor-Cohen et al. 2001). Based on the collective evidence, the p.Ile1173Phe variant is classified as pathogenic for Dubin-Johnson syndrome. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population.
Eurofins Ntd Llc (ga) RCV000727693 SCV000855036 pathogenic not provided 2018-03-27 criteria provided, single submitter clinical testing
Baylor Genetics RCV000008929 SCV001521393 pathogenic Dubin-Johnson syndrome 2019-09-06 criteria provided, single submitter clinical testing This variant was determined to be pathogenic according to ACMG Guidelines, 2015 [PMID:25741868].
Invitae RCV000727693 SCV003263529 pathogenic not provided 2024-01-31 criteria provided, single submitter clinical testing This sequence change replaces isoleucine, which is neutral and non-polar, with phenylalanine, which is neutral and non-polar, at codon 1173 of the ABCC2 protein (p.Ile1173Phe). This variant is present in population databases (rs72558201, gnomAD 0.004%). This missense change has been observed in individuals with Dubin-Johnson syndrome (PMID: 11477083, 31544333). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 8418). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt ABCC2 protein function with a positive predictive value of 80%. Experimental studies have shown that this missense change affects ABCC2 function (PMID: 11477083, 12388192, 22290738). For these reasons, this variant has been classified as Pathogenic.
OMIM RCV000008929 SCV000029139 pathogenic Dubin-Johnson syndrome 2001-10-05 no assertion criteria provided literature only
FirmaLab, FirmaLab RCV000008929 SCV000106041 pathogenic Dubin-Johnson syndrome no assertion criteria provided clinical testing

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