ClinVar Genomic variation as it relates to human health

Variant summary: PURA c.697_699delTTC (p.Phe233del) results in an in-frame deletion that is predicted to remove the third Phenylalanine in a run of three Phenylalanines located in the "presumed functional domain of PURA which is necessary for homodimerisation in crystallography studies (Hunt_2014). " The variant was absent in 251468 control chromosomes (gnomAD). c.697_699delTTC has been reported in the literature in multiple individuals affected with mental retardation and delays in cognitive development (Hunt_2014, Tanaka_2015, Strauss_2017, Lee_2018, Reijnders_2018). All the patients presented the mutation as a de novo occurrence. These data indicate that the variant is very likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Three ClinVar submissions (evaluation after 2014) cite the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.

The Phe233del variant in PURA has been reported in 8 patients with autosomal dominat PURA syndrome, characterized by moderate to severe intellectual disability (ID) and several early-onset issues including motor delay, hypotonia, feeding difficulties, hyperthermia, hypersomnolence, hypoventilation/apneas, speech delay and abnormal nonepileptic movements. Other less common manifestations include congenital heart defects, skeletal, urogenital, ophthalmological, gastrointestinal, and endocrine abnormalities; soft skin was also described as well as craniofacial dysmorphism (Reijnders et al., 1993; Hunt et al., 2014; Tanaka et al., 2015; Reijnders et al., 2018; Lee et al., 2018). p.Phe233del falls in the third PUR domain that mediate dimerization, and is predicted to cause local folding defects (Reijnders et al., 2018). Its putative pathogenicy was estimated through 3 different in silico prediction algorithms (SIFT, PROVEAN, MutPred Indel) that agreed to define p.phe233del as pathogenetic

In-frame deletion of 1 amino acid in a non-repeat region; In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; Not observed in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 27148565, 25342064, 29150892, 28726809, 31028937, 29097605, 31273778, 33275834)

For these reasons, this variant has been classified as Pathogenic. Experimental studies and prediction algorithms are not available or were not evaluated, and the functional significance of this variant is currently unknown. ClinVar contains an entry for this variant (Variation ID: 189319). This variant has been observed in individual(s) with developmental delay, cortical visual impairment, and hypotonia (PMID: 25342064, 27148565). In at least one individual the variant was observed to be de novo. This variant is not present in population databases (gnomAD no frequency). This variant, c.697_699del, results in the deletion of 1 amino acid(s) of the PURA protein (p.Phe233del), but otherwise preserves the integrity of the reading frame.

The variant is not observed in the gnomAD v2.1.1 dataset. Inframe deletion located in a nonrepeat region was predicted to change the length of the protein and disrupt normal protein function. The variant has been previously reported as de novo in similarly affected individuals (PMID: 25342064 ‚PMID: 29150892 ‚PMID: 29097605 ‚ PMID: 28726809, PMID: 27148565). Therefore, this variant is classified as Pathogenic according to the recommendation of ACMG/AMP guideline.

A Heterozygous Inframe indel variant c.690_692delCTT in Exon 1 of the PURA gene that results in the amino acid substitution p.Phe231del was identified. The observed variant is novel in gnomAD exomes and genomes, respectively. The severity of the impact of this variant on the protein is medium, based on the effect of the protein and REVEL score . Rare Exome Variant Ensemble Learner (REVEL) is an ensembl method for predicting the pathogenicity of missense variants based on a combination of scores from 13 individual tools: MutPred, FATHMM v2.3, VEST 3.0, PolyPhen-2, SIFT, PROVEAN, MutationAssessor, MutationTaster, LRT, GERP++, SiPhy, phyloP, and phastCons. The REVEL score for an individual missense variant can range from 0 to 1, with higher scores reflecting greater likelihood that the variant is disease-causing. ClinVar has also classified this variant as Pathogenic/LikelyPathogenic (ClinVar ID: 189319). The Phe233del variant in PURA has been reported in 8 patients with autosomal dominat PURA syndrome, characterized by moderate to severe intellectual disability (ID) and several early-onset issues including motor delay, hypotonia, feeding difficulties, hyperthermia, hypersomnolence, hypoventilation/apneas, speech delay and abnormal nonepileptic movements. p.Phe233del falls in the third PUR domain that mediate dimerization, and is predicted to cause local folding defects (Reijnders MRF et al., 2018 and Hunt D et al., 2014). Based on the above evidence this variant has been classified as Pathogenic according to the ACMG guidelines.

This variant has been previously reported as a de novo change in patients with intellectual disability, motor and cognitive delays hypotonia, feeding difficulties and seizures (PMID: 27148565, 31273778, 25342064). The c.697_699del (p.Phe233del) variant affects a highly conserved phenylalanine residue in the PUR repeat III which has been implicated in the dimerization of two PURA molecules (PMID: 19846792). It is absent from the gnomAD population database and thus is presumed to be rare. Analysis of the parental samples was negative for the variant, indicating this variant likely occurred as a de novo event. However, low-level parental mosaicism cannot be excluded. Based on the available evidence, the c.697_699del (p.Phe233del) variant is classified as Pathogenic.

The PURA c.697_699delTTC variant is predicted to result in an in-frame deletion (p.Phe233del). This variant has been reported de novo in multiple individuals with PURA syndrome (Hunt et al. 2014. PubMed ID: 25342064; Tanaka et al. 2015. PubMed ID: 27148565; Strauss et al. 2018. PubMed ID: 28726809; Reijnders et al. 2018. PubMed ID: 29097605; Lee et al. 2018. PubMed ID: 29150892; Borlot et al. 2019. PubMed ID: 31273778; Cinquina et al. 2021. PubMed ID: 33275834). This variant has not been reported in a large population database (http://gnomad.broadinstitute.org), indicating this variant is rare. This variant is interpreted as pathogenic.