ClinVar Genomic variation as it relates to human health

Published functional studies demonstrate a damaging effect (insertion of a 6-bp intronic sequence causing a premature stop codon and nonsense-mediated mRNA decay) (Kobayashi et al., 2016); Not observed in large population cohorts (gnomAD); In silico analysis supports a deleterious effect on splicing; This variant is associated with the following publications: (PMID: 33490948, 26482601, 28881385)

PVS1_very strong;PS3_strong;PM2_supporting;PM6_moderate;BP4_supporting

The de novo heterozygous c.2347-7A>G splice region variant identified in the SETD5 gene has been reported in at least 4 individuals affected with a neurological disorder [PMID: 26482601; PMID:28881385]. Patients' clinical presentations included cognitive delay, growth retardation, autism spectrum disorder, attention deficit hyperactivity disorder, unsteady gait, heart defects, and craniofacial dysmorphism [PMID: 26482601; PMID:28881385]. Analysis of cDNA obtained from a patient derived lymphoblastoid cell lineshowed that this splice region variant introduces premature stop codon and the mutant mRNA is subjected to nonsense mediated decay [PMID: 26482601]. This variant has been reported as Pathogenic in ClinVar database by two independent laboratories [Variation ID:280376]. This variant is absent from gnomAD suggesting it is an extremely rare allele in the populations represented in this database. Based on the available evidence, the de novo c.2347-7A>G splice region variant identified in the SETD5 gene is reported as Pathogenic.

A Heterozygous Splice site region variant c.2347-7A>G in Exon 16 of the SETD5 gene that results in the amino acid substitution 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 high, 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 (ClinVar ID: 280376). Published functional studies demonstrate a damaging effect (insertion of a 6-bp intronic sequence causing a premature stop codon and nonsense-mediated mRNA decay). Patients clinical presentations included cognitive delay, growth retardation, autism spectrum disorder, attention deficit hyperactivity disorder, unsteady gait, heart defects, and craniofacial dysmorphism (Kobayashi Y et al., 2016, Powis Z et al., 2018). Based on the above evidence this variant has been classified as Pathogenic according to the ACMG guidelines.

Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with intellectual developmental disorder, autosomal dominant 23 (MIM#615761). (I) 0107 - This gene is associated with autosomal dominant disease. (I) 0115 - Variants in this gene are known to have variable expressivity. Some mildly affected parents with the same SETD5 variant as their more severely affected children have been reported (PMID: 28881385, 27375234). (I) 0210 - Splice site variant proven to affect splicing of the transcript with a known effect on protein sequence. Published functional studies using RT-PCR and next generation sequencing on a patient-derived lymphoblastoid cell line identified a 6bp insertion within the intronic sequence, introducing a premature stop codon and resulting in subsequent nonsense-mediated mRNA decay (PMID: 26482601). (SP) 0251 - This variant is heterozygous. (I) 0301 - Variant is absent from gnomAD (both v2 and v3). (SP) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. This variant has been reported as pathogenic in at least 11 individuals with SETD5-related features, six of which were confirmed de novo (ClinVar, PMIDs: 26482601, 28881385). (SP) 1203 - This variant has been shown to be de novo in the proband (parental status confirmed) (by trio analysis). (SP) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign