ClinVar Miner

Submissions for variant NM_000152.5(GAA):c.2105G>C (p.Arg702Pro) (rs398123172)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
EGL Genetic Diagnostics,Eurofins Clinical Diagnostics RCV000728685 SCV000856289 likely pathogenic not provided 2017-08-16 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV001193012 SCV001361536 uncertain significance not specified 2019-07-01 criteria provided, single submitter clinical testing Variant summary: GAA c.2105G>C (p.Arg702Pro) affects a highly conserved nucleotide and results in a non-conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 222484 control chromosomes (gnomAD). c.2105G>C has been reported in the literature in compound heterozygosity with a pathogenic GAA variant in an individual affected with Glycogen Storage Disease Type 2 (Pompe Disease), but limited information was provided on the case (Rajab_2015). These data therefore do not allow unequivocal conclusions about variant significance. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. However, a variant affecting the same nucleotide but leading to a different missense change (c.2105G>A/p.Arg702His) has been classified by our laboratory as pathogenic. In addition, other variants affecting the same codon have been reported in affected individuals (c.2104C>T (p.Arg702Cys), c.2105G>T (p.Arg702Leu); in ClinVar and HGMD) suggesting a functional importance for this location. One clinical diagnostic laboratory has submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation, and classified the variant as likely pathogenic. Based on the evidence outlined above, the variant was classified as VUS-possibly pathogenic.

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