Submissions for variant NM_000053.4(ATP7B):c.3243+5G>A

gnomAD frequency: 0.00010  dbSNP: rs373193482

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000441386	SCV000512211	uncertain significance	not provided	2022-12-28	criteria provided, single submitter	clinical testing	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)
Genome-Nilou Lab	RCV001785612	SCV002027158	uncertain significance	Wilson disease	2021-09-05	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV002298584	SCV002598838	uncertain significance	not specified	2022-09-12	criteria provided, single submitter	clinical testing	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.
Fulgent Genetics, Fulgent Genetics	RCV001785612	SCV002778963	uncertain significance	Wilson disease	2021-12-22	criteria provided, single submitter	clinical testing
Invitae	RCV001785612	SCV003245921	uncertain significance	Wilson disease	2022-09-27	criteria provided, single submitter	clinical testing	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.
Revvity Omics, Revvity	RCV001785612	SCV003834475	likely pathogenic	Wilson disease	2023-07-11	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV001785612	SCV004216439	uncertain significance	Wilson disease	2023-04-10	criteria provided, single submitter	clinical testing
Mayo Clinic Laboratories, Mayo Clinic	RCV000441386	SCV004226441	uncertain significance	not provided	2023-05-09	criteria provided, single submitter	clinical testing	BP4, PP4, PM3
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV001785612	SCV004564336	uncertain significance	Wilson disease	2022-12-23	criteria provided, single submitter	clinical testing	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.