ClinVar Genomic variation as it relates to human health

This nonsense mutation is categorized as deleterious according to ACMG guidelines (PMID:18414213). It was found once in our laboratory de novo in a 5-year-old male with global delays, autism, microcephaly, dysmorphic features, ptosis

Published functional studies demonstrate a loss of function effect (Dang et al., 2017; Blackburn et al., 2019); Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 34345024, 25641759, 26922654, 25944381, 25920557, 31263215, 32581362, 25167861, 28167836, 32838606, 33562844, 35873028, 35285131)

The heterozygous p.Arg205Ter variant in DYRK1A was identified by our study in one individual with intellectual disability, feeding difficulties, and dysmorphic facial features. The p.Arg205Ter variant in DYRK1A has been previously reported in the literature in 10 unrelated individuals with DYRK1A-related intellectual disability syndrome (PMID: 25326635, PMID: 25944381, PMID: 25641759, PMID: 25167861, PMID: 32838606, PMID: 28167836, PMID: 32581362, PMID: 25920557). The number of reported affected individuals with this variant is greater than expected compared to non-affected individuals with this variant. This variant was found to be de novo in 9 individuals with confirmed paternity and maternity (PMID: 25326635, PMID: 25944381, PMID: 25641759, PMID: 25167861, PMID: 32838606, PMID: 28167836, PMID: 25920557, SCV002521469.1, SCV000196058.1). This variant has also been reported in ClinVar (Variation ID: 162153) and has been interpreted as pathogenic by multiple submitters. This variant was absent from large population studies. In vitro functional studies provide some evidence that the p.Arg205Ter variant may impact protein function (PMID 28167836, PMID: 31263215). However, these types of assays may not accurately represent biological function. This nonsense variant leads to a premature termination codon at position 205, which is predicted to lead to a truncated or absent protein. Heterozygous loss of function of the DYRK1A gene is an established disease mechanism in autosomal dominant DYRK1A-related intellectual disability syndrome. In summary, this variant meets criteria to be classified as pathogenic for autosomal dominant DYRK1A-related intellectual disability syndrome. ACMG/AMP Criteria applied: PVS1, PS2_VeryStrong, PS3_Moderate, PS4, PM2_Supporting (Richards 2015).

The alteration results in a premature stop codon:_x000D_ _x000D_ The c.613C>T (p.R205*) alteration, located in coding exon 5 of the DYRK1A gene, results from a C to T substitution at nucleotide position 613. This changes the amino acid from a arginine (R) to a stop codon at amino acid position 205. This alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. The alteration is not observed in population databases:_x000D_ _x000D_ Based on data from the Genome Aggregation Database (gnomAD), the DYRK1A NM_001396 c.613C>T alteration was not observed, with coverage at this position. The alteration has been observed in affected individuals:_x000D_ _x000D_ This alteration was reported to have occurred de novo in multiple individuals with features consistent with a DYRK1A-related neurodevelopmental disorder including intellectual disability/developmental delay, seizures, microcephaly and dysmorphic facial features (Redin, 2014; Ruaud, 2015; Ji, 2015). Based on the available evidence, this alteration is classified as pathogenic.

The variant is not observed in the gnomAD v2.1.1 dataset. Stop-gained (nonsense): predicted to result in a loss or disruption of normal protein function through nonsense-mediated decay (NMD) or protein truncation. Multiple pathogenic variants are reported downstream of the variant. The variant has been reported at least twice as pathogenic with clinical assertions and evidence for the classification (ClinVar ID: VCV000162153 / PMID: 25167861). Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline.

This sequence change creates a premature translational stop signal (p.Arg205*) in the DYRK1A gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in DYRK1A are known to be pathogenic (PMID: 25944381). This variant is not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individual(s) with DYRK1A-related disease (PMID: 25167861, 25641759, 25920557, 25944381; Invitae). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 162153). For these reasons, this variant has been classified as Pathogenic.