Submissions for variant NM_001127178.3(PIGG):c.2778_2782del (p.Cys927fs)

Total submissions: 2

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV003066737	SCV003446709	likely pathogenic	Intellectual disability, autosomal recessive 53	2022-06-19	criteria provided, single submitter	clinical testing	This sequence change results in a frameshift in the PIGG gene (p.Cys927Tyrfs*58). While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 57 amino acid(s) of the PIGG protein. This variant is present in population databases (no rsID available, gnomAD 0.003%). This variant has not been reported in the literature in individuals affected with PIGG-related conditions. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. This variant disrupts the C-terminus of the PIGG protein. Other variant(s) that disrupt this region (p.Tyr934*, p.Tyr957*) have been observed in individuals with PIGG-related conditions (PMID: 34113002). This suggests that this may be a clinically significant region of the protein. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.
Pittsburgh Clinical Genomics Laboratory, University of Pittsburgh Medical Center	RCV003066737	SCV005397472	likely pathogenic	Intellectual disability, autosomal recessive 53	2023-07-28	criteria provided, single submitter	clinical testing	This sequence variant is a deletion of 4 nucleotides in exon 13 of 13 of the PIGG gene which results in an early termition codon 58 amino acids downstream of the frameshift at codon 927. As it occurs in the fil exon, the variant transcript is not predicted to be targeted by nonsense-mediated decay; however, the fil 57 amino acids of the protein are altered. This is a previously reported variant (ClinVar 2140007) that has not been observed in the literature in individuals affected by PIGG-related disease, to our knowledge. This variant is present in 1 of 251448 alleles (0.0004%) in the gnomAD population dataset. Truncating PIGG variants downstream of this one are considered to be pathogenic (PMID: 34113002, ClinVar). Based upon the evidence, we consider this variant to be likely pathogenic. ACMG Criteria: PM2, PVS1