NM_002055.5:c.259G>C

Variant names:

• chr17-44915228-C-G
• rs267607518
• NM_002055.5:c.259G>C

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PM2 PP3_Moderate PP5_Very_Strong

The NM_002055.5(GFAP):​c.259G>C​(p.Val87Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: GFAP NM_002055.5 missense
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:2 O:2
• Conservation: PhyloP100: 7.73

Genes affected

GFAP (HGNC:4235): (glial fibrillary acidic protein) This gene encodes one of the major intermediate filament proteins of mature astrocytes. It is used as a marker to distinguish astrocytes from other glial cells during development. Mutations in this gene cause Alexander disease, a rare disorder of astrocytes in the central nervous system. Alternative splicing results in multiple transcript variants encoding distinct isoforms. [provided by RefSeq, Oct 2008]

ACMG classification

Verdict is Pathogenic. Variant got 12 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.938
• PP5: Variant 17-44915228-C-G is Pathogenic according to our data. Variant chr17-44915228-C-G is described in ClinVar as [Pathogenic]. Clinvar id is 66477.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GFAP	NM_002055.5	c.259G>C	p.Val87Leu	missense_variant	Exon 1 of 9	ENST00000588735.3	NP_002046.1
GFAP	NM_001363846.2	c.259G>C	p.Val87Leu	missense_variant	Exon 1 of 10		NP_001350775.1
GFAP	NM_001242376.3	c.259G>C	p.Val87Leu	missense_variant	Exon 1 of 7		NP_001229305.1
GFAP	NM_001131019.3	c.259G>C	p.Val87Leu	missense_variant	Exon 1 of 8		NP_001124491.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GFAP	ENST00000588735.3	c.259G>C	p.Val87Leu	missense_variant	Exon 1 of 9	1	NM_002055.5	ENSP00000466598.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:2 Other:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Alexander disease Pathogenic:2 Other:1

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GeneReviews

Significance: not provided

Review Status: no classification provided

Collection Method: literature only

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Feb 13, 2019

Illumina Laboratory Services, Illumina

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

Jan 23, 2024

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

not provided Other:1

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Epithelial Biology; Institute of Medical Biology, Singapore

Significance: not provided

Review Status: no classification provided

Collection Method: literature only

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Pathogenic	0.54	D
BayesDel_noAF	Pathogenic	0.54
CADD	Pathogenic	30
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.97	.;D;.;.;.;D;.;.;.
Eigen	Uncertain	0.64
Eigen_PC	Uncertain	0.57
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.99	D;D;D;D;D;D;D;D;D
M_CAP	Pathogenic	0.46	D
MetaRNN	Pathogenic	0.94	D;D;D;D;D;D;D;D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	4.5	.;H;.;H;H;.;.;.;.
PrimateAI	Uncertain	0.74	T
PROVEAN	Uncertain	-2.6	.;.;D;D;.;.;.;.;.
REVEL	Pathogenic	0.93
Sift	Uncertain	0.0010	.;.;D;D;.;.;.;.;.
Sift4G	Uncertain	0.0020	.;.;D;D;.;D;D;.;.
Polyphen		0.67	.;P;.;.;.;.;.;.;.
Vest4		0.96, 0.97, 0.98
MutPred		0.80		Loss of methylation at K86 (P = 0.0363);Loss of methylation at K86 (P = 0.0363);Loss of methylation at K86 (P = 0.0363);Loss of methylation at K86 (P = 0.0363);Loss of methylation at K86 (P = 0.0363);Loss of methylation at K86 (P = 0.0363);Loss of methylation at K86 (P = 0.0363);Loss of methylation at K86 (P = 0.0363);Loss of methylation at K86 (P = 0.0363);
MVP		1.0
MPC		0.93
ClinPred		1.0	D
GERP RS		3.7
Varity_R		0.91
gMVP		0.97

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs267607518; hg19: chr17-42992596;