ClinVar Genomic variation as it relates to human health

This variant is interpreted as a Likely pathogenic for Turnpenny-Fry syndrome, autosomal dominant. The following ACMG Tag(s) were applied: PM2, PS4-Moderate, PM6.

Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 30343942, 28628100, 28867141, 28135719, 31278258, 27535533, 31785789, 34750959, 25533962)

This sequence change replaces proline, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 65 of the PCGF2 protein (p.Pro65Leu). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with clinical features of Turnpenny-Fry syndrome (PMID: 30343942). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 619193). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt PCGF2 protein function with a negative predictive value of 80%. For these reasons, this variant has been classified as Pathogenic.

The heterozygous p.Pro65Leu variant in PCGF2 has been identified as de novo in at least four individuals including this patient being tested (PMID: 25533962, DECIPHER database, Broad Institute Rare Genomes Project) all with overlapping features of intellectual disability, external ear abnormalities, and dysmorphic features. It is absent from the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org). Additionally, the proline (Pro) at position 65 is highly conserved in mammals and evolutionarily distant species, suggesting that a change at this position may be disruptive. A mouse model with a complete homozygous knockout of this gene leads to early death of mice, suggesting the gene is critical for humans; however, heterozygotes were normal and no model is available for the Pro65Leu variant which may act through a distinct gain of function mechanism. In summary, with four independant de novo observations of this variant in individuals with overlapping phenotypes, we believe this variant is Likely Pathogenic for this individual's condition which includes non-verbal intellectual disability, autism, hypotonia, camptodactly, scoliosis, chronic constipation, GERD, mild cortical vision impairment, low set crumpled ears, mildly dilated aorta, and life-threatening food allergies.

The c.194C>T (p.P65L) alteration is located in exon 4 (coding exon 2) of the PCGF2 gene. This alteration results from a C to T substitution at nucleotide position 194, causing the proline (P) at amino acid position 65 to be replaced by a leucine (L). This variant was not reported in population-based cohorts in the Genome Aggregation Database (gnomAD). This variant has been identified as a recurrent de novo variant in multiple individuals with Turnpenny-Fry syndrome with features including a recognizable facial gestalt, intellectual disability, feeding problems, impaired growth, and a range of brain, cardiovascular, and skeletal abnormalities (Turnpenny, 2018; Ambry internal data). In one family, this variant was detected as mosaic in the asymptomatic mother (Turnpenny, 2018). This amino acid position is highly conserved in available vertebrate species. This alteration is predicted to be tolerated by in silico analysis. Based on the available evidence, this alteration is classified as pathogenic.

The heterozygous p.Pro65Leu variant in PCGF2 has been identified as de novo in at least four individuals including this patient being tested (PMID: 25533962, DECIPHER database, Broad Institute Rare Genomes Project) with overlapping features of intellectual disability, external ear abnormalities, and dysmorphic features. It is absent from the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org). Additionally, the proline (Pro) at position 65 is highly conserved in mammals and in evolutionarily distant species, suggesting that a change at this position may be disruptive. A mouse model with a complete homozygous knockout of this gene leads to early death of mice, suggesting the gene is critical for humans; however, heterozygotes were normal and no model is available for the Pro65Leu variant which may act through a distinct gain of function mechanism. In summary, with four independent de novo observations of this variant in individuals with overlapping phenotypes, we believe this variant is likely pathogenic for this individual's condition which includes non-verbal intellectual disability, autism, hypotonia, camptodactly, scoliosis, chronic constipation, GERD, mild cortical vision impairment, low set crumpled ears, mildly dilated aorta, and life-threatening food allergies.