Submissions for variant NM_002055.5(GFAP):c.1154C>G (p.Ser385Cys)

gnomAD frequency: 0.00001  dbSNP: rs797044590

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000479686	SCV000567528	pathogenic	not provided	2015-08-27	criteria provided, single submitter	clinical testing	The S385C variant in the GFAP gene has been reported previously in a father and son with Alexanderdisease (Graff-Radford et al., 2014). This substitution has not been observed in approximately 6,500 individualsof European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not acommon benign variant in these populations. The S385C variant is a non-conservative amino acidsubstitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge,size and/or other properties. Additionally, this substitution occurs at a position where amino acids with similarproperties to Serine are tolerated across species, and other missense variants nearby and at the same position(S385F) have been reported in the Human Gene Mutation Database in association with Alexander disease(Stenson et al., 2014; Zang et al., 2013). In silico analysis predicts this variant is probably damaging to theprotein structure/function. Therefore, we interpret S385C as a pathogenic variant.
Mayo Clinic Laboratories, Mayo Clinic	RCV000479686	SCV001712923	likely pathogenic	not provided	2020-12-18	criteria provided, single submitter	clinical testing	PM2, PM5, PP1, PP4
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000192180	SCV001983549	likely pathogenic	Alexander disease	2021-09-28	criteria provided, single submitter	clinical testing	Variant summary: GFAP c.1154C>G (p.Ser385Cys) results in a non-conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 205884 control chromosomes. c.1154C>G has been reported in the literature in individuals affected with Alexander Disease or multiple sclerosis (Graff-Radford_2014, Le_2017). These data indicate that the variant is likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Three clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as likely pathogenic.
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	RCV000192180	SCV002767944	pathogenic	Alexander disease	2021-05-06	criteria provided, single submitter	clinical testing	Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as pathogenic. Following criteria are met: 0105 - The mechanism of disease for this gene is not clearly established. The mechanism of disease for this gene is not clearly established. Functional studies have demonstrated both dominant negative and gain of function are possible mechanisms of disease, however, the latter is the more widely accepted mechanism (OMIM, PMIDs: 11138011, 30355500, 31484723, 20301351).(I) 0107 - This gene is associated with autosomal dominant disease. (I) 0115 - Variants in this gene are known to have variable expressivity (PMID: 20301351). (I) 0200 - Variant is predicted to result in a missense amino acid change from serine to cysteine. (I) 0251 - This variant is heterozygous. (I) 0302 - Variant is present in gnomAD (v3) <0.001 for a dominant condition (1 heterozygote, 0 homozygotes). (SP) 0501 - Missense variant consistently predicted to be damaging by multiple in silico tools and highly conserved with a major amino acid change. (SP) 0601 - Variant is located in the functional important C-terminal domain. Mutant constructs harbouring C-terminal GFAP variants identified in affected individuals resulted in protein self-aggregation compared to wild type GFAP protein. Co-transfection of mutant and wild type constructs also resulted in increased filament aggregation relative to the amount of mutant construct. However, these experiments were performed in cancer cell ines and may not represent the best experimental model to investigate filament assembly (PMID: 21756903). (SP) 0704 - Another missense variant comparable to the one identified in this case has limited previous evidence for pathogenicity. The p.S385F variant has been reported in two individuals with infantile Alexander disease (PMIDs: 23364391, 22818990). (SP) 0802 - This variant has moderate previous evidence of pathogenicity in unrelated individuals. This variant has been reported in four individuals with adult Alexander disease (PMIDs: 24306001, 26285664, Le S. and Soileau M. 2017, ClinVar). (SP) 0906 - Segregation evidence for this variant is inconclusive. There is insufficient information to determine the segregation of this variant with disease. (I) 1007 - No published functional evidence has been identified for this variant. (I) 1102 - Strong phenotype match for this individual. (SP) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign
Labcorp Genetics (formerly Invitae), Labcorp	RCV000479686	SCV003306058	pathogenic	not provided	2023-05-08	criteria provided, single submitter	clinical testing	For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Ser385 amino acid residue in GFAP. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 22818990, 23364391). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on GFAP protein function. ClinVar contains an entry for this variant (Variation ID: 190362). This missense change has been observed in individuals with clinical features of Alexander disease (PMID: 24306001, 26285664; Invitae). It has also been observed to segregate with disease in related individuals. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces serine, which is neutral and polar, with cysteine, which is neutral and slightly polar, at codon 385 of the GFAP protein (p.Ser385Cys).
CeGaT Center for Human Genetics Tuebingen	RCV000479686	SCV004009807	likely pathogenic	not provided	2023-08-01	criteria provided, single submitter	clinical testing	GFAP: PM2, PM5, PS4:Moderate, PP3
GeneReviews	RCV000192180	SCV000223046	not provided	Alexander disease		no assertion provided	literature only