ClinVar Genomic variation as it relates to human health

Variant summary: The GAA c.447G>A (p.Thr149Thr) variant involves the alteration of a non-conserved nucleotide, resulting in a synonymous change that is not located in any known domain (InterPro). One in silico tool predicts a damaging outcome for this variant. 5/5 splice prediction tools predict no significant impact on normal splicing. However, these predictions have yet to be confirmed by functional studies. This variant was found in 1372/272790 control chromosomes (12 homozygotes) at a frequency of 0.0050295, which is approximately equal to the estimated maximal expected allele frequency of a pathogenic GAA variant (0.0042205), suggesting this variant is likely a benign polymorphism. In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as benign. The variant of interest has not, to our knowledge, been reported in affected individuals via publications and/or reputable databases/clinical diagnostic laboratories; nor evaluated for functional impact by in vivo/vitro studies. Taken together, this variant is classified as benign.

This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease.

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease.

The c.447G>A (p.Thr149=) variant in GAA has been reported in one individual with Glycogen Storage Disease Type II (PMID: 18458862). This variant has been reported as a benign variant (by UChicago Genetics Services Laboratory, GeneDx, Invitae, EGL, and PreventionGenetics) and a VUS (by Illumina) in ClinVar (Variation ID: 129121). This variant has been identified in 2.97% (590/19862) of East Asian chromosomes and 13 homozygotes as well as other populations at lesser frequencies by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs2289536). This variant has been seen in the general population at a frequency high enough to rule out a pathogenic role. Computational prediction tools, including splice predictors, and conservation analyses suggest that this variant may not impact the protein, though this information is not predictive enough to rule out pathogenicity. In summary, this variant meets criteria to be classified as benign for Glycogen Storage Disease II in an autosomal recessive manner based on its frequency in the general population. ACMG/AMP Criteria applied: BA1, BP7, BP4 (Richards 2015).