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NM_002055.5(GFAP):c.676G>A (p.Val226Met) AND not provided

Germline classification:
Conflicting interpretations of pathogenicity (2 submissions)
Last evaluated:
Apr 22, 2022
Review status:
criteria provided, conflicting classifications
Somatic classification
of clinical impact:
None
Review status:
(0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided
Somatic classification
of oncogenicity:
None
Review status:
(0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided
Record status:
current
Accession:
RCV000992077.9

Allele description [Variation Report for NM_002055.5(GFAP):c.676G>A (p.Val226Met)]

NM_002055.5(GFAP):c.676G>A (p.Val226Met)

Gene:
GFAP:glial fibrillary acidic protein [Gene - OMIM - HGNC]
Variant type:
single nucleotide variant
Cytogenetic location:
17q21.31
Genomic location:
Preferred name:
NM_002055.5(GFAP):c.676G>A (p.Val226Met)
HGVS:
  • NC_000017.11:g.44913373C>T
  • NG_008401.1:g.7174G>A
  • NM_001131019.3:c.676G>A
  • NM_001242376.3:c.676G>A
  • NM_001363846.2:c.676G>A
  • NM_002055.5:c.676G>AMANE SELECT
  • NP_001124491.1:p.Val226Met
  • NP_001229305.1:p.Val226Met
  • NP_001350775.1:p.Val226Met
  • NP_002046.1:p.Val226Met
  • NC_000017.10:g.42990741C>T
  • NC_000017.10:g.42990741C>T
  • NM_002055.4:c.676G>A
Protein change:
V226M
Links:
dbSNP: rs149883728
NCBI 1000 Genomes Browser:
rs149883728
Molecular consequence:
  • NM_001131019.3:c.676G>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001242376.3:c.676G>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001363846.2:c.676G>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_002055.5:c.676G>A - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Synonyms:
none provided
Identifiers:
MedGen: C3661900

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Assertion and evidence details

Help
Submission AccessionSubmitterReview Status
(Assertion method)		Clinical Significance
(Last evaluated)		OriginMethodCitations
SCV001144053Athena Diagnostics
criteria provided, single submitter

(Athena Diagnostics Criteria)		Likely benign
(Apr 25, 2019) 		germlineclinical testing

PubMed (1)
[See all records that cite this PMID]

SCV002137081Labcorp Genetics (formerly Invitae), Labcorp
criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))		Uncertain significance
(Apr 22, 2022) 		germlineclinical testing

PubMed (1)
[See all records that cite this PMID]

Help

Summary from all submissions

EthnicityOriginAffectedIndividualsFamiliesChromosomes testedNumber TestedFamily historyMethod
not providedgermlineunknownnot providednot providednot providednot providednot providedclinical testing

Citations

PubMed

A Standardized DNA Variant Scoring System for Pathogenicity Assessments in Mendelian Disorders.

Karbassi I, Maston GA, Love A, DiVincenzo C, Braastad CD, Elzinga CD, Bright AR, Previte D, Zhang K, Rowland CM, McCarthy M, Lapierre JL, Dubois F, Medeiros KA, Batish SD, Jones J, Liaquat K, Hoffman CA, Jaremko M, Wang Z, Sun W, Buller-Burckle A, et al.

Hum Mutat. 2016 Jan;37(1):127-34. doi: 10.1002/humu.22918. Epub 2015 Oct 29.

PubMed [citation]
PMID:
26467025
PMCID:
PMC4737317

Sherloc: a comprehensive refinement of the ACMG-AMP variant classification criteria.

Nykamp K, Anderson M, Powers M, Garcia J, Herrera B, Ho YY, Kobayashi Y, Patil N, Thusberg J, Westbrook M; Invitae Clinical Genomics Group., Topper S.

Genet Med. 2017 Oct;19(10):1105-1117. doi: 10.1038/gim.2017.37. Epub 2017 May 11. Erratum in: Genet Med. 2020 Jan;22(1):240. doi: 10.1038/s41436-019-0624-9.

PubMed [citation]
PMID:
28492532
PMCID:
PMC5632818

Details of each submission

From Athena Diagnostics, SCV001144053.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (1)
#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineunknownnot providednot providednot providednot providednot providednot providednot provided

From Labcorp Genetics (formerly Invitae), Labcorp, SCV002137081.3

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (1)

Description

This sequence change replaces valine, which is neutral and non-polar, with methionine, which is neutral and non-polar, at codon 226 of the GFAP protein (p.Val226Met). This variant is present in population databases (rs149883728, gnomAD 0.03%), and has an allele count higher than expected for a pathogenic variant. This variant has not been reported in the literature in individuals affected with GFAP-related conditions. ClinVar contains an entry for this variant (Variation ID: 804868). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Deleterious"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0". The methionine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.

#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineunknownnot providednot providednot providednot providednot providednot providednot provided

Last Updated: Sep 29, 2024