ClinVar Genomic variation as it relates to human health

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 in large population cohorts (Lek et al., 2016); This variant is associated with the following publications: (PMID: 28135719, 27915094, 25533962, 28191890)

ACMG criteria used to clasify this variant: PVS1, PM2_SUP

Based on the classification scheme VCGS_Germline_v0.6.1, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss of function is a known mechanism of disease for this gene. (N) 0104 - Mechanism of disease for this gene is dominant negative. (N) 0107 - This gene is known to be associated with autosomal dominant disease. (N) 0201 - Variant is predicted to cause nonsense-mediated decay (NMD) and loss of protein (exon 13 of 15). (P) 0301 - Variant is absent from gnomAD. (P) 0401 - Variant is located in a gene associated with a severe early onset dominant condition that is intolerant to loss-of-function variants. (P) 0702 - Comparable variant in relevant codon/region has strong previous evidence for pathogenicity. Other variants predicted to cause NMD have been reported as pathogenic in individuals with this condition (ClinVar). (P) 0802 - Moderate previous evidence of pathogenicity in unrelated individuals. It has been previously reported in patients with neurodevelopmental disorder with spastic diplegia and visual defects (ClinVar; Decipher; LOVD; PMID: 27848944). (P) 0905 - No published segregation evidence has been identified for this variant. (N) 1007 - No published functional evidence has been identified for this variant. (N) 1208 - Inheritance information for this variant is not currently available. (N) Legend: (P) - Pathogenic, (N) - Neutral, (B) - Benign

This nonsense variant found in exon 13 of 15 is predicted to result in loss of normal protein function through either protein truncation or nonsense-mediated mRNA decay (NMD). This variant has been previously reported as a de novo heterozygous change in patients with intellectual disability, neurodevelopmental disorder, dysmorphic features, motor delay, short stature, speech delay, and autistic features (PMID: 27915094, 25533962, 28191890, 28135719, 31785789). Missense variation at the same amino acid residue has been previously reported in individuals with autism and neurodevelopmental delay (PMID: 31785789, 31981491). Loss-of-function variation in CTNNB1 is an established mechanism of disease (PMID: 27915094, 35593792). The c.1981C>T (p.Arg661Ter) variant 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. Based on the available evidence, the c.1981C>T (p.Arg661Ter) variant is classified as Pathogenic.

For these reasons, this variant has been classified as Pathogenic. Loss-of-function variants in CTNNB1 are known to be pathogenic (PMID: 23033978, 24614104, 25326669, 26350204). This variant has been reported to be de novo in an individual affected with microcephaly, developmental delay and other CTNNB1-related phenotypes (PMID: 27915094). ClinVar contains an entry for this variant (Variation ID: 429824). This variant is not present in population databases (ExAC no frequency). This sequence change creates a premature translational stop signal (p.Arg661*) in the CTNNB1 gene. It is expected to result in an absent or disrupted protein product.