ClinVar Genomic variation as it relates to human health

In silico analysis supports that this variant does not alter splicing; This variant is associated with the following publications: (PMID: 32248359, 34324271, 23518715, 24517292, 33640437, 23551039)

Variant summary: ATP7B c.3243+5G>A 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. Several computational tools predict a significant impact on normal splicing: Three predict the variant weakens a canonical 5' donor site and one predicts the variant has no significant impact on splicing. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 0.00039 in 248946 control chromosomes (gnomAD). This frequency is not significantly higher than expected for a pathogenic variant in ATP7B causing Wilson Disease (0.00039 vs 0.0054), allowing no conclusion about variant significance. c.3243+5G>A has been reported in the literature in multiple compound heterozygous individuals affected with Wilson Disease (e.g. Aggarwal_2013, Ferenci_2014, Collins_2021, Xiao_2021). These data indicate that the variant may be associated with disease. Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 and classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as VUS - possibly pathogenic.

This sequence change falls in intron 14 of the ATP7B gene. It does not directly change the encoded amino acid sequence of the ATP7B protein. It affects a nucleotide within the consensus splice site. This variant is present in population databases (rs373193482, gnomAD 0.2%). This variant has been observed in individual(s) with Wilson disease (PMID: 23518715, 23551039, 24517292, 34324271). ClinVar contains an entry for this variant (Variation ID: 377539). Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant is not likely to affect RNA splicing. 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.

BP4, PP4, PM3

The ATP7B c.3243+5G>A variant (rs373193482) is reported in the literature in compound heterozygous individuals diagnosed with Wilson disease (Aggarwal 2013, Collins 2021, Ferenci 2014). This variant is also reported in ClinVar (Variation ID: 377539). It is observed in the general population with an overall allele frequency of 0.03% (98/280296 alleles) in the Genome Aggregation Database. This is an intronic variant in a weakly conserved nucleotide, but computational analyses (Alamut v.2.11) predict that this variant may impact splicing by weakening the nearby canonical donor splice site. However, due to the lack of functional data, the clinical significance of this variant is uncertain at this time. References: Aggarwal A et al. Wilson disease mutation pattern with genotype-phenotype correlations from Western India: confirmation of p.C271* as a common Indian mutation and identification of 14 novel mutations. Ann Hum Genet. 2013 Jul;77(4):299-307. PMID: 23551039. Collins CJ et al. Direct Measurement of ATP7B Peptides Is Highly Effective in the Diagnosis of Wilson Disease. Gastroenterology. 2021 Jun;160(7):2367-2382.e1. PMID: 33640437. Ferenci P. Phenotype-genotype correlations in patients with Wilson's disease. Ann N Y Acad Sci. 2014 May;1315:1-5. PMID: 24517292.

This variant causes a G to A nucleotide substitution at the +5 position of intron 14 of the ATP7B gene. Splice site prediction tools predict that this variant may have a significant impact on RNA splicing. Although this prediction has not been confirmed in published RNA studies, this variant is expected to result in an absent or disrupted protein product. To our knowledge, functional studies have not been reported for this variant. This variant has been reported in the compound heterozygous state in individuals affected with Wilson disease (PMID: 23551039, 34324271). This variant has been identified in 98/280296 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.

Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as VUS-3A. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated Wilson disease (MIM#277900). (I) 0106 - This gene is associated with autosomal recessive disease. (I) 0212 - Non-canonical splice site variant without proven consequence on splicing (no functional evidence available). (SP) 0252 - This variant is homozygous. (I) 0304 - Variant is present in gnomAD (v2) <0.01 for a recessive condition (98 heterozygotes, 0 homozygotes). (SP) 0311 - An alternative nucleotide change at the same splice site, is present in gnomAD (v2: 2 heterozygotes, 0 homozygotes). (I) 0506 - Abnormal splicing is not predicted and nucleotide is moderately conserved. (I) 0710 - Another non-canonical splice variant comparable to the one identified in this case has inconclusive previous evidence for pathogenicity. The alternative change (c.3243+5G>C) has been reported as a VUS in ClinVar. (I) 0809 - Previous evidence of pathogenicity for this variant is inconclusive. This variant has been reported multiple times as a VUS in ClinVar and in at least five individuals with Wilson's Disease with a second variant, although phasing was not confirmed (PMID: 23551039, PMID: 24517292, PMID: 34324271, PMID: 36112267). (I) 1209 - This variant has been shown to be both maternally and paternally inherited (biallelic; by trio analysis). (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign