ClinVar Genomic variation as it relates to human health

This variant is interpreted as a Likely pathogenic for Neurodevelopmental disorder with or without variable brain abnormalities, autosomal dominant. The following ACMG Tag(s) were applied: PM2, PM6, PP3, PS3-Moderate, PS4-Supporting.

This variant was identified as de novo (maternity and paternity confirmed).

The MAPK8IP3 c.1732C>T (p.Arg578Cys) variant is a missense variant that has been reported in five individuals, including two siblings, all with neurodevelopmental phenotypes including hypoplasia of the corpus callosum, intellectual disability, developmental delays, short stature, white matter abnormalities, language delays, and spasticity. Seizures, microcephaly, facial features including a round face and thin upper lip, and obesity were also noted in some of the individuals (Iwasawa et al. 2019; Platzer et al. 2019). The p.Arg578Cys variant occurred de novo in all cases including the two siblings, suggesting possible germline mosaicism in a parent. In a zebrafish model, expression of the p.Arg578Cys variant protein showed axon varicosities while wild type axons had a smooth surface, suggesting a negative effect on axon development (Iwasawa et al. 2019). The p.Arg578Cys variant is absent from the Genome Aggregation Database in a region of good sequence coverage, so the variant is presumed to be rare. Based on the collective evidence, the p.Arg578Cys variant is classified as pathogenic for MAPK8IP3-related neurodevelopmental disorder.

Same nucleotide change resulting in same amino acid change has been previously reported as de novo and observed in at least four similarly affected unrelated individuals (3billion dataset, ClinVar ID: VCV000632564.11, PMID: 30945334 and 30612693, PS2 and PS4). It is not observed in the gnomAD v2.1.1 dataset (PM2). The variant was observed as assumed (i.e. paternity and maternity not confirmed) de novoo (3billion dataset, PM6). In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.811, 3Cnet: 0.882, PP3). Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline.

Published functional studies demonstrate a damaging effect suggesting adverse effect on the developing axon (PMID: 30945334); Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 30612693, 30945334, 36066546, 35982159, 33057194)

Based on the classification scheme VCGS_Germline_v1.1.1, this variant is classified as pathogenic. Following criteria are met: 0102 - Loss-of-function is a known mechanism of disease for this gene. (N) 0107 - This gene is known to be associated with autosomal dominant disease. (N) 0200 - Variant is predicted to result in a missense amino acid change from arginine to cysteine (exon 16). (N) 0251 - Variant is heterozygous. (N) 0301 - Variant is absent from gnomAD. (P) 0309 - An alternative amino acid change at the same position has been observed in gnomAD (1 heterozygote, 0 homozygotes). (N) 0501 - Missense variant consistently predicted to be damaging by multiple in silico tools or highly conserved with a major amino acid change. (P) 0600 - Variant is located in an annotated domain or motif, (RH2 domain; PDB). (N) 0705 - No comparable variants have previous evidence for pathogenicity. (N) 0801 - Strong previous evidence of pathogenicity in multiple de novo, unrelated individuals with a neurological syndrome or intellectual disability (ClinVar, Decipher, PMID: 30612693, PMID: 30945334). (P) 0905 - No segregation evidence has been identified for this variant. (N) 1002 - Moderate functional evidence supporting abnormal protein function. Zebrafish transfected with mutant protein displayed abnormal axons (PMID: 30945334). (P) 1208 - Inheritance information for this variant is not currently available. (N) Legend: (P) - Pathogenic, (N) - Neutral, (B) - Benign

The p.Arg578Cys variant in the MAPK8IP3 gene has been previously reported de novo in 5 individuals from 4 families with features consistent with neurodevelopmental disorder with or without variable brain abnormalities (Iwasawa et al., 2019; Platzer et al., 2019). This variant was absent from large population databases, including the Genome Aggregation Database (http://gnomad.broadinstitute.org/). Computational tools predict that the p.Arg578Cys variant is deleterious; however, the accuracy of in silico algorithms is limited. These data were assessed using the ACMG/AMP variant interpretation guidelines. In summary, there is sufficient evidence to classify the p.Arg578Cys variant as pathogenic for autosomal dominant neurodevelopmental disorder with or without variable brain abnormalities based on the information above. [ACMG evidence codes used: PS2_verystrong; PM2; PP3]

Variant confirmed as disease-causing by referring clinical team