ClinVar Genomic variation as it relates to human health

Converted during submission to Uncertain significance.

This variant was classified as: Uncertain significance. The following ACMG criteria were applied in classifying this variant: PM2,PP2,PM5.

NM_000053.3(ATP7B):c.4301C>T(T1434M) is a missense variant classified as a variant of uncertain significance in the context of Wilson disease. T1434M has been observed in cases with relevant disease (PMID 29482223, 18483695, 10544227, 22484412, 32154060). Functional assessments of this variant are available in the literature (PMID: 14962673, 21454443). T1434M has been observed in population frequency databases (gnomAD: ASJ 0.91%). In summary, there is insufficient evidence to classify NM_000053.3(ATP7B):c.4301C>T(T1434M) as pathogenic or benign. Please note: this variant was assessed in the context of healthy population screening.

Variant summary: ATP7B c.4301C>T (p.Thr1434Met) results in a non-conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.002 in 249530 control chromosomes, including 1 homozygote, in the gnomAD database (v 2.1 exomes dataset). The variant was observed predominantly within the African or African-American subpopulation at a frequency of 0.0053. This frequency is close to the maximum expected for a pathogenic variant in ATP7B causing Wilson Disease (0.0053 vs. 0.0054), suggesting that the variant might be benign. The variant, c.4301C>T, has been reported in the literature in individuals affected with Wilson Disease (Loudianos_1999, Abdelghaffar_2008, Lepori_2012) and other disease phenotypes (e.g. Vasta_2012, Demily_2017, Coutelier_2018). However, co-occurrences with other pathogenic variant have been reported (ATP7B homozygous c.3809A>G (p.Asn1270Ser); Abdelghaffar_2008) that could explain the patient's phenotype, thus providing supporting evidence for a benign role. A recent study found the variant in French residents, who were treated with indications other than Wilson Disease (WD), hepatic or neurological diseases, at a frequency of 0.00645 (i.e. 9/1394 alleles), whereas the variant was not found in their WD database, which included 496 index cases. Publications also reported experimental evidence evaluating an impact on protein function, and showed no damaging effect for this variant (Braiterman_2011, Hsi_2003). Multiple clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation, and classified the variant as VUS (n=8) or likely benign (n=3). Based on the evidence outlined above, the variant was classified as likely benign.

The p.Thr1323Met variant in ATP7B (also described as p.Thr1434Met) has been reported in at least 1 heterozygous individual and 1 homozygous individual with Wilson disease; however the homozygous individual was also homozygous for a known pathogenic variant in ATP7B (Loudianos 1999, Abdel Ghaffar 2008, Abdel Ghaffar 2011). This variant has also been reported in ClinVar (Variation ID#35730). This variant was also reported in 4 heterozygous individuals with other neuropsychiatric diseases and were not observed to have typical Wilson disease features (Bell 2011 and Demily 2017). In vitro functional studies in yeast do not suggest copper transport or complementation are impaired (Hsi 2004); however, these types of assays may not accurately represent biological function. This variant has been identified in 0.877% (89/10150) of Ashkenazi Jewish chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs60986317). In summary, due to its population frequency and functional data and findings with other pathogenic variants, the p.Thr1323Met variant is classified as likely benign. ACMG/AMP Criteria applied: BS3, BP4 (Richards 2015).

ATP7B: BP4, BS2