ClinGen Dosage Sensitivity Curation Page


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Evidence for Loss Phenotypes

Evidence for loss of function phenotype
PubMed ID Description
23033978 de Ligt et al (NEJM, 2012) performed family-based diagnostic exome sequencing to evaluate role of de novo as well as X linked inherited variants among 100 patients with unexplained intellectual disability (including unaffected parents). All patients had undergone genomic microarray (250K Affymetrix SNP array) as well as targeted gene tests, with metabolic screening, however these evaluations did not lead to a diagnosis. One nonsense de novo mutation in exon 30 of 42 of PHIP Chr6(GRCh37):g.79672902A>C; PHIP:c.3447T>G; p.(Tyr1149*), was identified in a girl (ID in paper: trio 5) with developmental delay and facial dysmorphism, however MRI of the brain showed no abnormalities. Of the three categories of genes cataloged in this paper, known intellectual-disability (ID) genes, novel ID genes, and candidate ID genes; the mutation in PHIP fell into the last category (Table S3, S10). The authors assert that this is not a known ID gene, similar nonsense mutations in this gene have not been reported, and the mutational change is not at an evolutionary conserved genomic base (Table S3). Although the mRNA produced might be targeted for nonsense mediated decay, no additional functional studies were performed by the authors. At the time of submission by the authors in ClinVar, the p.(Tyr1149*) change has been listed as a variant of uncertain significance (submission ID: SCV000056894).
27900362 Webster et al (Cold Spring Harb Mol Case Stud 2016) studied 2522 patient with developmental delay or intellectual disability using whole exome sequencing. The authors identified two patients with novel de novo heterozygous variants in PHIP. These included a frameshift deletion NM_017934.6(PHIP):c.779del; p.Leu260Trpfs*48 in exon 8 and a missense variant NM_017934.6(PHIP):c.50T>C; p.Phe17Ser in exon 2 in two unrelated individuals. Both patients are girls with overlapping phenotypes similar to the previously reported patient with a de novo heterozygous nonsense mutation in PHIP, p.Y1149* (PMID 1: 23033978). This included developmental delay, intellectual disability, anxiety, hypotonia, obesity, and dysmorphic facial features. No brain malformations were observed. Neither variant was observed in ExAC and in silco tools predicted conflicting effects of pathogenicity for the highly conserved missense, p.F17S, variant (tolerant by SIFT and disease causing by MutationTaster). Of note, the patient with the missense variant also had an additional genetic variant reported as a 95-kb paternally inherited 5q23.2 duplication, including CEP120 and CSNK1G3 genes. Overall the authors point out that PHIP has a high haploinsufficiency score [p(HI) = 0.95], albeit based on a predictive model (PMID: 20976243) and is also intolerant to loss-of-function variants [(p(LI) = 1.00]. Both variants were reported in ClinVar as likely pathogenic (accession ID: SCV000282078 for the frameshift and SCV000282077 for the missense -- assertion method based on GeneDx variant classification guidelines).
27824329 Wang et al (Nature Communications 2016) explored spectrum of de novo mutations in ASD risk genes among the Chinese population. The authors analyzed 189 autism risk genes across 1,543 autism probands (1,045 trios) applying single-molecule molecular inversion probes to the coding regions for targeted sequencing. The autism risk genes were selected based on the frequency and severity of de novo mutations from previously published exome sequencing studies. 43 de novo mutations in 29 of the 189 candidate genes were identified. Although PHIP did not exhibit recurrent mutations, a de novo likely gene disruptive 2 basepair deletion [NM_017934.6(PHIP):c.5300_5301del] in exon 40 was detected in one individual from their autism cohort (supp table 7 and HGMD entry) and predicted to cause a frameshift at codon Arg1767 (Alamut). Functional studies or detailed phenotype information on this individual was not provided and IQ data was not readily collected on their cohort.

Evidence for Triplosenstive Phenotype

NOTE:The loss of function score should be used to evaluate deletions, and the triplosensitivity score should be used to evaluated duplications. CNVs encompassing more than one gene must be evaluated in their totality (e.g. overall size, gain vs. loss, presence of other genes, etc). The rating of a single gene within the CNV should not necessarily be the only criteria by which one defines a clinical interpretation. Individual interpretations must take into account the phenotype described for the patient as well as issues of penetrance and expressivity of the disorder. ACMG has published guidelines for the characterization of postnatal CNVs, and these recommendations should be utilized (Genet Med (2011)13: 680-685). Exceptions to these interpretive correlations will occur, and clinical judgment should always be exercised.