Total submissions: 2
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Invitae | RCV001887346 | SCV002159140 | uncertain significance | not provided | 2022-06-27 | criteria provided, single submitter | clinical testing | This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 406 of the ABCB4 protein (p.Arg406Gln). This variant is present in population databases (rs763807769, gnomAD 0.002%). This missense change has been observed in individual(s) with low-phospholipid-associated cholelithiasis syndrome (PMID: 20537830, 22331132, 23533021). It has also been observed to segregate with disease in related individuals. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive. 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. |
| Women's Health and Genetics/Laboratory Corporation of America, |
RCV002307787 | SCV002600867 | uncertain significance | not specified | 2022-10-04 | criteria provided, single submitter | clinical testing | Variant summary: ABCB4 c.1217G>A (p.Arg406Gln) results in a conservative amino acid change located in the ABC transporter-like, ATP-binding domain (IPR003439) of the encoded protein sequence. Four 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 251204 control chromosomes. c.1217G>A has been reported in the literature as a biallelic compound heterozygous genotype in at-least two individuals from a single family affected with features of Familial Intrahepatic Cholestasis with subsequent citations by others (example, Poupon_2010, cited by Wendum_2012, Khabou_2017, Khabou_2019, Wang_2022). These data indicate that the variant may be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. 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. |