Table 2 GCM2 variants classification according to the ACMG guidelines.
From: Five patients with disorders of calcium metabolism presented with GCM2 gene variants
Gene | Nucleotide change* | Amino acid change* | Selected criteria for pathogenic variants | Selected criteria for benign variants | Variant class |
|---|---|---|---|---|---|
GCM2 | c.943A>G | p.Asn315Asp | PS3: Well-established in vitro functional studies supportive of a damaging effect on the gene product (20% more activity than wild-type protein) | BP6: Reputable source recently reports variant as benign but the evidence is not available to the laboratory to perform an independent evaluation (Reported in ClinVar as benign) | Uncertain significance |
GCM2 | c.1144G>A | p.Val382Met | PS3: Well-established in vitro functional studies supportive of a damaging effect on the gene product (2.1 times higher activity than wild-type protein) PM1: Located in a well-established functional domain (CCID) PP5: Reported as pathogenic | – | Likely pathogenic |
GCM2 | c.1185_1186insGCCTACCAG | p.Ala393_Gln395dup | PM1: Located in a well-established functional domain (CCID) PM4: Protein length changes as a result of in-frame duplication in a non-repeat region | BS1: Allele frequency is greater than expected for disorder BS3: Well-established in vitro functional studies show no damaging effect on protein function BP6: Reputable source recently reports variant as benign but the evidence is not available to the laboratory to perform an independent evaluation (Reported in ClinVar as benign and likely benign) | Benign |
GCM2 | c.1460C>T | p.(Ser487Phe) | PM1: Located in a well-established functional domain (TAD2) PM2: Absent from controls in Exome Sequencing Project, 1000 Genomes Project, or Exome Aggregation Consortium (ExAC) | – | Uncertain significance |
