Submissions for variant NM_002055.5(GFAP):c.262C>T (p.Arg88Cys)

dbSNP: rs61622935

Total submissions: 10

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000056879	SCV000329358	pathogenic	not provided	2024-02-20	criteria provided, single submitter	clinical testing	In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 17629821, 16505300, 34865968, 36088400, 17318298, 11567214, 26478912, 15477559, 15732097, 12034785, 18079314, 16217707, 17894839, 34146839, 35831840, 31069529, 36601294)
Athena Diagnostics	RCV000056879	SCV001475137	pathogenic	not provided	2019-09-30	criteria provided, single submitter	clinical testing	Not found in the total gnomAD dataset, and the data is high quality. Predicted to have a damaging effect on the protein. Assessment of experimental evidence regarding the effect of this variant on protein function is inconclusive. 10 de novo cases with parental identity not confirmed.
3billion	RCV000017555	SCV002059015	pathogenic	Alexander disease	2022-01-03	criteria provided, single submitter	clinical testing	Same nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000016172, PS1_S). Functional studies provide strong evidence of the variant having a damaging effect on the gene or gene product (PMID: 17318298, PS3_S). In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.942, 3CNET: 0.966, PP3_P). A missense variant is a common mechanism associated with Alexander disease (PP2_P). It is not observed in the gnomAD v2.1.1 dataset (PM2_M). The variant is located in a well-established functional domain or exonic hotspot, where pathogenic variants have frequently reported (PM1_M). A different missense change at the same codon has been reported to be associated with GFAP related disorder (ClinVar ID: VCV000016173, PM5_P).Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline.
Invitae	RCV000056879	SCV002117900	pathogenic	not provided	2022-08-16	criteria provided, single submitter	clinical testing	For these reasons, this variant has been classified as Pathogenic. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive. ClinVar contains an entry for this variant (Variation ID: 16172). This missense change has been observed in individual(s) with Alexander disease (PMID: 11567214, 15732097, 26478912). 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 cysteine, which is neutral and slightly polar, at codon 88 of the GFAP protein (p.Arg88Cys).
Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein	RCV000017555	SCV003807314	pathogenic	Alexander disease	2022-10-28	criteria provided, single submitter	clinical testing	ACMG classification criteria: PS1 strong, PS3 supporting, PS4 strong, PM2 moderated, PM6 moderated, PP3 supporting
CeGaT Center for Human Genetics Tuebingen	RCV000056879	SCV004041999	pathogenic	not provided	2023-09-01	criteria provided, single submitter	clinical testing	GFAP: PM6:Strong, PM1, PM2, PM5, PS4:Moderate, PP4, PS3:Supporting
Kasturba Medical College, Manipal, Kasturba Medical College, Manipal, Manipal Academy of Higher Education, Manipal, India	RCV000017555	SCV005088180	pathogenic	Alexander disease		criteria provided, single submitter	clinical testing
OMIM	RCV000017555	SCV000037827	pathogenic	Alexander disease	2001-11-01	no assertion criteria provided	literature only
Epithelial Biology; Institute of Medical Biology, Singapore	RCV000056879	SCV000087992	not provided	not provided		no assertion provided	not provided
GeneReviews	RCV000017555	SCV000222979	not provided	Alexander disease		no assertion provided	literature only