ClinVar Miner

Submissions for variant NM_000053.4(ATP7B):c.4135C>T (p.Pro1379Ser) (rs181250704)

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Total submissions: 10
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Genetic Services Laboratory, University of Chicago RCV000309770 SCV000192359 uncertain significance not specified 2017-03-23 criteria provided, single submitter clinical testing
EGL Genetic Diagnostics,Eurofins Clinical Diagnostics RCV000587055 SCV000331180 uncertain significance not provided 2017-05-17 criteria provided, single submitter clinical testing
GeneDx RCV000587055 SCV000520721 uncertain significance not provided 2018-07-20 criteria provided, single submitter clinical testing The P1379S variant in the ATP7B gene has been reported previously in the compound heterozygous state, opposite of the H1069Q pathogenic variant, in a toddler with elevated AST, whose mother had Wilson disease and was homozygous for the H1069Q variant (Bennett et al., 2013). The P1379S variant was also identified in another individual with Wilson disease; however, it is unknown if a second variant in ATP7B was identified in this individual, and additional clinical information was not provided (Cox et al., 2005). Functional analysis of P1379S found that it is associated with normal transport activity and trafficking (Braiterman et al., 2011). The P1379S variant is observed in 225/124,250 (0.18%) alleles from individuals of non-Finnish European background in large population cohorts (Lek et al., 2016). The P1379S variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. We interpret P1379S as a variant of uncertain significance.
Integrated Genetics/Laboratory Corporation of America RCV000309770 SCV000694464 uncertain significance not specified 2019-04-05 criteria provided, single submitter clinical testing Variant summary: ATP7B c.4135C>T (p.Pro1379Ser) results in a non-conservative amino acid change located after the TM8 domain 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 274588 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) . Additionally, it was reported in a study among individuals who had no family history or indications of of WD (Collet_2018). 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_2018). Five clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories RCV000587055 SCV000885053 uncertain significance not provided 2017-05-10 criteria provided, single submitter clinical testing
Fulgent Genetics,Fulgent Genetics RCV000763902 SCV000894839 uncertain significance Wilson disease 2018-10-31 criteria provided, single submitter clinical testing
Invitae RCV000763902 SCV001016601 likely benign Wilson disease 2019-12-31 criteria provided, single submitter clinical testing
Mendelics RCV000763902 SCV001139346 uncertain significance Wilson disease 2019-05-28 criteria provided, single submitter clinical testing
CeGaT Praxis fuer Humangenetik Tuebingen RCV000587055 SCV001156175 uncertain significance not provided 2016-11-01 criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,Illumina RCV000763902 SCV001267651 uncertain significance Wilson disease 2018-02-20 criteria provided, single submitter clinical testing 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.

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