ClinVar Miner

Submissions for variant NM_007144.3(PCGF2):c.194C>T (p.Pro65Leu) (rs1567941252)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
SIB Swiss Institute of Bioinformatics RCV000766184 SCV000996450 likely pathogenic Turnpenny-fry syndrome 2019-07-16 criteria provided, single submitter curation 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.
Broad Institute Rare Disease Group, Broad Institute RCV000758165 SCV000886439 likely pathogenic Abnormality of the outer ear; Intellectual disability 2018-03-29 no assertion criteria provided research 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, 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.
OMIM RCV000766184 SCV000897615 pathogenic Turnpenny-fry syndrome 2019-03-28 no assertion criteria provided literature only
Equipe Genetique des Anomalies du Developpement, Université de Bourgogne RCV000766184 SCV001190251 pathogenic Turnpenny-fry syndrome 2019-05-13 no assertion criteria provided clinical testing
Génétique des Maladies du Développement, Hospices Civils de Lyon RCV001255407 SCV001431807 likely pathogenic Global developmental delay 2019-11-01 no assertion criteria provided clinical testing

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