ClinVar Genomic variation as it relates to human health

Functional analysis found that it is associated with normal transport activity and trafficking (PMID: 21454443); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 14962673, 28392828, 25741868, 16472602, 33848968, 32685348, 17680703, 32248359, 34426522, 24253677, 30254379, 30097039, 23430806, 35626323, 34620762, 16088907, 21454443, 37660282, 33972609, 37937776, 30476936)

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.

ACMG classification criteria: PM2, PP3

Variant summary: ATP7B c.4135C>T (p.Pro1379Ser) results in a non-conservative amino acid change located in the after the TM8 domain (Tang_2019) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.0011 in 247012 control chromosomes in the gnomAD database, including 1 homozygote. This frequency is not significantly higher than expected for a pathogenic variant in ATP7B causing Wilson Disease (0.0011 vs 0.0054), allowing no conclusion about variant significance. c.4135C>T has been reported in the literature in at-least one individual affected with Wilson Disease (Cox_2005) and as a compound heterozygote in an unaffected newborn with a genotype (H1069Q/P1379S) from a family in which the affected proband was homozygous for the other well reported variant (H1069Q/H1069Q) (Bennett_2013). It was also reported in a study among individuals who had no family history or indications of of WD (Collet_2018). Additionally, it was found in four compound heterozygous children with one known pathogenic variant and remain asymptomatic without abnormal laboratory consequences (Yi_2020). Lastly, this variant has been reported in a recent study describing the global prevalence of Wilson disease as one among five most frequently known disease variants citing Cox_2005 (Gao_2018). These data do not allow any conclusion about variant significance. At least one publication reports experimental evidence evaluating an impact on protein function. These results showed no damaging effect of this variant on copper transport, protein stability or copper-responsive trafficking (Braiterman_2011). 13 ClinVar submitters (evaluation after 2014) cite the variant as uncertain significance (n=11) and likely benign (n=1) and benign (n=1). Based on the evidence outlined above, the variant was classified as uncertain significance.

This missense variant replaces proline with serine at codon 1379 of the ATP7B protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). However, functional studies have shown that this variant did not impact protein expression, copper transport and trafficking, and oxidase activity (PMID: 14962673, 21454443). This variant has been observed in the compound heterozygous state in individuals affected with autosomal recessive Wilson disease (PMID: 16088907, 23430806, 32685348). This variant has been identified in 311/278336 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.

The ATP7B c.4135C>T; p.Pro1379Ser variant (rs181250704) is reported in the literature in an individual with Wilson disease (Cox 2005). This variant was detected in trans with a pathogenic variant in four children from two families (Bennett 2013; Yi 2020); since there is significant variation in age of presentation in patients with Wilson disease (Weiss 2016), it is difficult to assess the significance of the reports of unaffected children currently. Functional analyses show the variant protein has normal transport activity (Braiterman 2011). This variant is listed in ClinVar (Variation ID: 157957), and is found in the general population with an overall allele frequency of 0.11% (311/278,336 alleles, including 1 homozygote) in the Genome Aggregation Database (v2.1.1). Computational analyses predict that this variant is deleterious (REVEL: 0.879). Although some evidence suggests ATP7B p.Pro1379Ser is not a deleterious variant, due limited clinical information on children harboring this variant in trans to a pathogenic ATP7B variant, its clinical significance cannot be determined with certainty at this time. References: Bennett JT et al. An exceptional family with three consecutive generations affected by Wilson disease. JIMD Rep. 2013;10:1-4. PMID: 23430806. Braiterman L et al. Critical roles for the COOH terminus of the Cu-ATPase ATP7B in protein stability, trans-Golgi network retention, copper sensing, and retrograde trafficking. Am J Physiol Gastrointest Liver Physiol. 2011 Jul;301(1):G69-81. PMID: 21454443. Cox DW et al. Twenty-four novel mutations in Wilson disease patients of predominantly European ancestry. Hum Mutat. 2005 Sep;26(3):280. PMID: 16088907. Weiss KH. Wilson Disease. 1999 Oct 22 [Updated 2016 Jul 29]. In: Adam MP, Everman DB, Mirzaa GM, et al., editors. GeneReviews [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2022. Available from: https://www.ncbi.nlm.nih.gov/books/NBK1512 Yi F et al. p.P1379S, a benign variant with reduced ATP7B protein level in Wilson Disease. JIMD Rep. 2020 May 19;54(1):32-36. PMID: 32685348.

This missense variant replaces proline with serine at codon 1379 of the ATP7B protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). Functional studies have shown that this variant had normal protein expression, copper transport and trafficking, and oxidase activity; similar to wild-type (PMID: 14962673, 21454443). This variant has been observed in many individuals affected with autosomal recessive Wilson disease (PMID: 16088907, 23430806, 32685348) all of which are compound heterozygous. This variant has been identified in 311/278336 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.

The p.P1379S variant (also known as c.4135C>T), located in coding exon 21 of the ATP7B gene, results from a C to T substitution at nucleotide position 4135. The proline at codon 1379 is replaced by serine, an amino acid with similar properties. This alteration was first described in an Italian patient diagnosed with Wilson disease; however, a second pathogenic alteration was not described (Cox DW et al. Hum. Mutat., 2005 Sep;26:280). In another study, p.P1379S was confirmed in trans with a pathogenic mutation in a child who, at 21 months was healthy, developing normally, and had normal ceruloplasmin levels (Bennett JT et al. JIMD Rep, 2013 Mar;10:1-4). A functional assay, using an hepatoma-derived hybrid cell line (WIF-B), showed that P1379S resulted in no dramatic defect in copper transport, protein stability, or copper-responsive trafficking when compared to wild-type (Braiterman L et al. Am. J. Physiol. Gastrointest. Liver Physiol., 2011 Jul;301:G69-81). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.

ATP7B: BS2

The ATP7B c.4135C>T variant is predicted to result in the amino acid substitution p.Pro1379Ser. This variant has been reported in the heterozygous state in an individual with Wilson disease, but it was unclear if a second causative allele was identified (Cox et al. 2005. PubMed ID: 16088907). It has also been reported in the compound heterozygous state in a child with suspected Wilson disease (Bennett et al. 2013. PubMed ID: 23430806). This variant has been reported as disease causing in a French cohort (Collet et al. 2018. PubMed ID: 30097039) and a meta-analysis of Wilson disease studies (Gao et al. 2019. PubMed ID: 30254379). However, functional studies suggest that this variant does not impact copper transport, protein stability, or copper-responsive trafficking (Braiterman et al. 2011. PubMed ID: 21454443). In ClinVar, the vast majority of clinical laboratories interpret this variant as uncertain significance (https://www.ncbi.nlm.nih.gov/clinvar/variation/157957/). At this time, the clinical significance of this variant is uncertain due to due to the lack of conclusive functional and genetic evidence.