ClinVar Genomic variation as it relates to human health

This sequence change affects codon 213 of the PGK1 mRNA. It is a 'silent' change, meaning that it does not change the encoded amino acid sequence of the PGK1 protein. This variant is not present in population databases (gnomAD no frequency). This variant has been observed in individual(s) with phosphoglycerate kinase 1 deficiency (PMID: 30111548). ClinVar contains an entry for this variant (Variation ID: 167466). Studies have shown that this variant is associated with altered splicing resulting in reduced mRNA expression (PMID: 17661373). For these reasons, this variant has been classified as Pathogenic.

Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with phosphoglycerate kinase 1 deficiency (MIM#300653). (I) 0109 - This gene is associated with X-linked recessive disease. (I) 0212 - Non-canonical splice site variant without proven consequence on splicing. (SP) 0253 - This variant is hemizygous. (I) 0301 - Variant is absent from gnomAD (v2, v3 and v4). (SP) 0705 - No comparable splice variants have previous evidence for pathogenicity. (I) 0802 - This variant has moderate previous evidence of pathogenicity in unrelated individuals. This variant has been reported as likely pathogenic, pathogenic, and as a VUS in ClinVar. Additionally, it has been observed as hemizygous in two brothers with exercise induced muscle stiffness and myoglobinuria, and as heterozygous in their mildly affected sister (PMIDs: 17661373, 10809925). (SP) 1001 - This variant has strong functional evidence supporting abnormal protein function. Quantitative PCR on blood samples from individuals heterozygous or hemizygous for this variant has shown that it results in a reduction of PGK1 mRNA expression (PMID: 17661373). (SP) 1205 - This variant has been shown to be maternally inherited (by trio analysis). (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign

The c.639C>T variant in the PGK1 gene has been reported previously in two brothers with phosphoglycerate kinase deficiency. They presented with muscle pain, cramps, and stiffness following heavy exercise. Their sister, who was heterozygous for the c.639C>T mutation, also experienced mild muscle stiffness during exercise (Svaasand et al., 2007). This splicing variant, which also results in a synonymous change (p.Gly213Gly), is predicted to destroy the canonical splice donor site in intron 6. The c.639C>T variant is predicted to induce a large splicing change (Xiong et al., 2014). The c.639C>T variant was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. The c.639C>T variant is a strong candidate for a disease-causing variant, however, the possibility it may be a rare benign variant cannot be excluded.