Submissions for variant NM_002055.5(GFAP):c.236G>A (p.Arg79His)

dbSNP: rs59285727

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000056869	SCV000565039	pathogenic	not provided	2023-03-23	criteria provided, single submitter	clinical testing	Published functional studies in mouse models and zebrafish demonstrate a damaging effect (Hagemann et al., 2006; Lee et al., 2017); Not observed in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 11567214, 12034785, 28882119, 31932408, 31956193, 35105675, 34950187, 34865968, 17065456, 11138011, 23364391, 23432455, 16168593, 19444543, 30134051, 31952467, 31942421, 34146839, 35231114, 35511821)
CeGaT Center for Human Genetics Tuebingen	RCV000056869	SCV001250437	pathogenic	not provided	2023-07-01	criteria provided, single submitter	clinical testing	GFAP: PS2, PM2, PM5, PP3, PS4:Supporting
Invitae	RCV000056869	SCV003442440	pathogenic	not provided	2023-03-10	criteria provided, single submitter	clinical testing	For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Arg79 amino acid residue in GFAP. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 11138011, 18584981, 23254569, 28882119). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. Experimental studies have shown that this missense change affects GFAP function (PMID: 17065456, 23432455, 28882119). 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) performed at Invitae indicates that this missense variant is expected to disrupt GFAP protein function. ClinVar contains an entry for this variant (Variation ID: 16170). This variant is also known as 250G>A R79H. This missense change has been observed in individual(s) with Alexander disease (PMID: 11138011, 16168593, 31942421, 31956193). In at least one individual the variant was observed to be de novo. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 79 of the GFAP protein (p.Arg79His).
Revvity Omics, Revvity	RCV000017553	SCV003818157	pathogenic	Alexander disease	2022-06-14	criteria provided, single submitter	clinical testing
OMIM	RCV000017553	SCV000037825	pathogenic	Alexander disease	2001-01-01	no assertion criteria provided	literature only
Epithelial Biology; Institute of Medical Biology, Singapore	RCV000056869	SCV000087982	not provided	not provided		no assertion provided	not provided
GeneReviews	RCV000017553	SCV000222968	not provided	Alexander disease		no assertion provided	literature only
UOSD Laboratory of Genetics & Genomics of Rare Diseases, Istituto Giannina Gaslini	RCV000017553	SCV001786708	pathogenic	Alexander disease	2021-08-15	no assertion criteria provided	research	White matter abnormalities Cognitive impairment Scoliosis/Hip dislocation