ClinVar Genomic variation as it relates to human health

The GFAP c.259G>C (p.Val87Leu) missense variant is located in the helical rod domain of GFAP. The p.Val87Leu variant that has been reported in one study, in which it is found in a heterozygous state in a 31-year-old woman with Alexander disease (Suzuki et al. 2012). This patient was noted to have tonic-clonic seizures with treatment via anticonvulsants beginning as early as 10 months of age. She later presented with regression in mental function around age 15 and gait disturbance at age 25. Based on a neurological assessment in adulthood, her overall phenotype included psychomotor regression, seizures, pendular nystagmus, dysarthria, dysphagia, cerebellar ataxia, spastic gait, urine incontinence, and eventual palatal tremor. A brain MRI showed atrophy of the medulla oblongata and mild cervical cord atrophy, deep white matter abnormalities, periventricular rim, and signal changes of the medulla oblongata and dentate hilum. A head CT after a fall identified calcification in the subcortical and cortical regions (Suzuki et al. 2012). The p.Val87Leu variant is not found in the Genome Aggregation Database. The helical rod domain or central helical domain of GFAP is critical for interfilament network formation, filament assembly, and stabilization of subunits (Yoshida et al. 2007). Based on the application of ACMG criteria, the p.Val87Leu variant is classified as pathogenic for Alexander disease.

The GFAP c.259G>C; p.Val87Leu variant (rs267607518; ClinVar Variation ID: 66477) has been reported in at least two individuals with clinical findings consistent with Alexander disease (Mura 2021, Suzuki 2012). Suzuki et al (2012) described a patient with onset of tonic-clonic seizures at 10 months of age, intellectual regression at 15 years, and gait disturbances at 25 years. MRI at age 30 revealed white matter abnormalities and atrophy of the medulla oblongata and spinal cord. Mura et al (2021) described a 24-year-old patient with normal developmental milestones, but with cognitive impairment and loss of ambulation at age 9. This variant has also been identified in at least two additional individuals in cohorts of patients recruited for leukodystrophy (Cohen 2020) or suspected neurogenetic condition (Salinas 2020), but neither were clinically characterized in detail. This variant is absent from the Genome Aggregation Database (v2.1.1), indicating it is not a common polymorphism. Computational analyses predict that this variant is deleterious (REVEL: 0.928). Additionally, other missense variants at this codon in GFAP (e.g., p.Val87Ile) have been reported in Alexander disease (selected reference: Yoshida 2011). Based on available information, this variant is considered to be pathogenic. References: Cohen L et al. Argentinian clinical genomics in a leukodystrophies and genetic leukoencephalopathies cohort: Diagnostic yield in our first 9 years. Ann Hum Genet. 2020 Jan;84(1):11-28. PMID: 31418856. Mura E et al. Alexander disease evolution over time: data from an Italian cohort of pediatric-onset patients. Mol Genet Metab. 2021 Dec;134(4):353-358. PMID: 34865968. Salinas V et al. The odyssey of complex neurogenetic disorders: From undetermined to positive. Am J Med Genet C Semin Med Genet. 2020 Dec;184(4):876-884. PMID: 33084218. Suzuki H et al. Late-onset Alexander disease with a V87L mutation in glial fibrillary acidic protein (GFAP) and calcifying lesions in the sub-cortex and cortex. J Neurol. 2012 Mar;259(3):457-61. PMID: 21822933. Yoshida T et al. Nationwide survey of Alexander disease in Japan and proposed new guidelines for diagnosis. J Neurol. 2011 Nov;258(11):1998-2008. PMID: 21533827.