Submissions for variant NM_001448.3(GPC4):c.1609C>T (p.Gln537Ter)

Total submissions: 2

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Neuberg Centre For Genomic Medicine, NCGM	RCV003340733	SCV004047411	uncertain significance	Keipert syndrome		criteria provided, single submitter	clinical testing	The frameshift variant c.1609C>T(p.Gln537Ter) in GPC4 gene has not been reported previously as a pathogenic variant nor as a benign variant, to our knowledge. The p.Gln537Ter variant is novel (not in any individuals) in gnomAD exomes and is novel (not in any individuals) in 1000 Genomes. This variant has not been reported to the ClinVar database. The nucleotide change c.1609C>T in GPC4 is predicted as conserved by GERP++ and PhyloP across 100 vertebrates. Loss of function variants have been previously reported to be disease causing. However since this variant is present in the last exon functional studies will be required to prove protein truncation. Hence the variant is classified as Uncertain Significance (VUS).
PreventionGenetics, part of Exact Sciences	RCV003397013	SCV004104526	likely pathogenic	GPC4-related disorder	2023-08-28	criteria provided, single submitter	clinical testing	The GPC4 c.1609C>T variant is predicted to result in premature protein termination (p.Gln537*). This variant is located within the terminal exon and is predicted to result in the deletion of the last 20 amino acids of GPC4. To our knowledge, this variant has not been reported in the literature or in a large population database (http://gnomad.broadinstitute.org), indicating this variant is rare. At PreventionGenetics, this variant was found to have occurred de novo in a male individual with Keipert syndrome (internal data). Two nonsense variants, p.Glu496* and p.Gln506*, which are upstream in the terminal exon, have been reported to be causative for Keipert syndrome. It was proposed that the reduced protein stability as well as the loss of functionally critical N-linked glycosylation p.Asn514 and glycosylphosphatidylinositol anchor p.Ser529 are the underlying loss-of-function mechanism of the two nonsense variants (Amor et al. 2019. PubMed ID: 30982611). The c.1609C>T (p.Gln537*) variant is interpreted as likely pathogenic.