VCV000180842.16 - ClinVar

NM_000169.3(GLA):c.801G>A (p.Met267Ile)

Germline

Classification

The aggregate germline classification for this variant, typically for a monogenic or Mendelian disorder as in the ACMG/AMP guidelines, or for response to a drug. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the aggregate classification.

(5)

Stars represent the aggregate review status, or the level of review supporting the aggregate germline classification for this VCV record. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. The number of submissions which contribute to this review status is shown in parentheses.

Pathogenic

criteria provided, multiple submitters, no conflicts

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

Identifiers

NM_000169.3(GLA):c.801G>A (p.Met267Ile)

Variation ID: 180842 Accession: VCV000180842.16

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: Xq22.1 X: 100653773 (GRCh37) [ NCBI UCSC ] X: 101398785 (GRCh38) [ NCBI UCSC ]

Timeline in ClinVar

	First in ClinVar Help The date this variant first appeared in ClinVar with each type of classification.	Last submission Help The date of the most recent submission for each type of classification for this variant.	Last evaluated Help The most recent date that a submitter evaluated this variant for each type of classification.
Germline	Feb 24, 2015	Feb 14, 2024	Jul 15, 2021

HGVS

Nucleotide	Protein	Molecular consequence
NM_000169.3:c.801G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_000160.1:p.Met267Ile	missense
NM_001199973.2:c.300+3328C>T		intron variant
NM_001199974.2:c.177+6963C>T		intron variant
NM_001406747.1:c.924G>A	NP_001393676.1:p.Met308Ile	missense
NM_001406748.1:c.801G>A	NP_001393677.1:p.Met267Ile	missense
NR_164783.1:n.880G>A		non-coding transcript variant
NR_176252.1:n.731G>A		non-coding transcript variant
NR_176253.1:n.938G>A		non-coding transcript variant
NC_000023.11:g.101398785C>T
NC_000023.10:g.100653773C>T
NG_007119.1:g.14179G>A
LRG_672:g.14179G>A
LRG_672t1:c.801G>A	LRG_672p1:p.Met267Ile
	P06280:p.Met267Ile

... more HGVS ... less HGVS

Protein change

M267I, M308I

Other names

p.M267I:ATG>ATA

Canonical SPDI

NC_000023.11:101398784:C:T

Functional consequence Help The effect of the variant on RNA or protein function, based on experimental evidence from submitters.

Global minor allele frequency (GMAF) Help The global minor allele frequency calculated by the 1000 Genomes Project. The minor allele at this location is indicated in parentheses and may be different from the allele represented by this VCV record.

Allele frequency Help The frequency of the allele represented by this VCV record.

Links

ClinGen: CA022081 UniProtKB: P06280#VAR_012419 dbSNP: rs730880451 VarSome

Genes

Gene	OMIM	ClinGen Gene Dosage Sensitivity Curation		Variation Viewer Help Links to Variation Viewer, a genome browser to view variation data from NCBI databases.	Related variants
Gene	OMIM	HI score Help The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team.	TS score Help The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team.		Within gene Help The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants.	All Help The number of variants in ClinVar for this gene, including smaller variants within the gene and larger CNVs that overlap or fully contain the gene.
GLA		Sufficient evidence for dosage pathogenicity	No evidence available	GRCh38 GRCh37	7	1257
RPL36A-HNRNPH2	-	-	-	GRCh38 GRCh37	-	1293

Conditions - Germline

Condition Help The condition for this variant-condition (RCV) record in ClinVar.	Classification Help The aggregate germline classification for this variant-condition (RCV) record in ClinVar. The number of submissions that contribute to this aggregate classification is shown in parentheses. (# of submissions)	Review status Help The aggregate review status for this variant-condition (RCV) record in ClinVar. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status.	Last evaluated Help The most recent date that a submitter evaluated this variant for the condition.	Variation/condition record Help The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page.
not provided	Pathogenic (2)	criteria provided, multiple submitters, no conflicts	Mar 21, 2018	RCV000157900.5
Fabry disease	Pathogenic (3)	criteria provided, multiple submitters, no conflicts	Jul 15, 2021	RCV000627818.14

Submissions - Germline

Classification Help The submitted germline classification for each SCV record. (Last evaluated)	Review status Help Stars represent the review status, or the level of review supporting the submitted (SCV) record. This value is calculated by NCBI based on data from the submitter. Read our rules for calculating the review status. This column also includes a link to the submitter’s assertion criteria if provided, and the collection method. (Assertion criteria)	Condition Help The condition for the classification, provided by the submitter for this submitted (SCV) record. This column also includes the affected status and allele origin of individuals observed with this variant.	Submitter Help The submitting organization for this submitted (SCV) record. This column also includes the SCV accession and version number, the date this SCV first appeared in ClinVar, and the date that this SCV was last updated in ClinVar.	More information Help This column includes more information supporting the classification, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter.
Pathogenic (Mar 21, 2018)	criteria provided, single submitter (EGL ClinVar v180209 classification definitions) Method: clinical testing	not provided Affected status: unknown Allele origin: germline	Eurofins Ntd Llc (ga) Accession: SCV000860476.1 First in ClinVar: Feb 24, 2015 Last updated: Feb 24, 2015	Other databases http://www.egl-eurofins.com/emvc… http://www.egl-eurofins.com/emvclass/emvclass.php?approved_symbol=GLA Number of individuals with the variant: 2 Sex: mixed
Pathogenic (Oct 31, 2018)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Fabry disease Affected status: unknown Allele origin: unknown	Fulgent Genetics, Fulgent Genetics Accession: SCV000893812.1 First in ClinVar: Mar 31, 2019 Last updated: Mar 31, 2019	Publications: PubMed (1) PubMed: 25741868 pmc: 4544753 pmc: 4544753 DOI: 10.1038/gim.2015.30 DOI: 10.1038/gim.2015.30
Pathogenic (Jul 15, 2021)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Fabry disease Affected status: no Allele origin: germline	Genome-Nilou Lab Accession: SCV002054404.1 First in ClinVar: Jan 12, 2022 Last updated: Jan 12, 2022
Pathogenic (May 15, 2019)	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015)) Method: clinical testing	Fabry disease Affected status: unknown Allele origin: germline	Labcorp Genetics (formerly Invitae), Labcorp Accession: SCV000748695.6 First in ClinVar: May 28, 2018 Last updated: Feb 14, 2024	Publications: PubMed (5) PubMed: 10666480‚ 11668641‚ 17576681‚ 9536098‚ 22773828 Comment: This variant has been reported in several individuals affected with Fabry disease (PMID: 10666480, 11668641, Invitae). ClinVar contains an entry for this variant (Variation ID: … (more) This variant has been reported in several individuals affected with Fabry disease (PMID: 10666480, 11668641, Invitae). ClinVar contains an entry for this variant (Variation ID: 180842). For these reasons, this variant has been classified as Pathogenic. Nucleotide substitutions within the consensus splice site are relatively common causes of aberrant splicing (PMID: 17576681, 9536098). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site, but this prediction has not been confirmed by published transcriptional studies. Experimental studies have shown that this missense change has a moderate effect on GLA protein aggregation but results in a reduction of GLA enzymatic activity in vitro (PMID: 22773828). This variant is not present in population databases (ExAC no frequency). This sequence change replaces methionine with isoleucine at codon 267 of the GLA protein (p.Met267Ile). The methionine residue is highly conserved and there is a small physicochemical difference between methionine and isoleucine. This variant also falls at the last nucleotide of exon 5 of the GLA coding sequence, which is part of the consensus splice site for this exon. (less)
Pathogenic (Jan 18, 2014)	criteria provided, single submitter (GeneDx Variant Classification (06012015)) Method: clinical testing	Not Provided Affected status: yes Allele origin: germline	GeneDx Accession: SCV000207831.10 First in ClinVar: Feb 24, 2015 Last updated: Feb 24, 2015	Comment: The M267I mutation in the GLA gene has been reported in a single patient with Fabry disease who was hemizygous for the mutation and had … (more) The M267I mutation in the GLA gene has been reported in a single patient with Fabry disease who was hemizygous for the mutation and had a plasma alpha-Gal A activity of 0.2U/ml (Topaloglu A et al., 1999). Other mutations affecting the same residue (M267R, M267T) as well as mutations in neighboring residues (D266V, D266E, L268S) have been reported in association with Fabry disease, further supporting the functional importance of this residue and this region of the protein. Furthermore, the M267I mutation was not observed inapproximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. In summary, M267I in the GLA gene is interpreted as a disease-causing mutation. The variant is found in HCM panel(s). (less)

Comment:

This variant has been reported in several individuals affected with Fabry disease (PMID: 10666480, 11668641, Invitae). ClinVar contains an entry for this variant (Variation ID: 180842). For these reasons, this variant has been classified as Pathogenic. Nucleotide substitutions within the consensus splice site are relatively common causes of aberrant splicing (PMID: 17576681, 9536098). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site, but this prediction has not been confirmed by published transcriptional studies. Experimental studies have shown that this missense change has a moderate effect on GLA protein aggregation but results in a reduction of GLA enzymatic activity in vitro (PMID: 22773828). This variant is not present in population databases (ExAC no frequency). This sequence change replaces methionine with isoleucine at codon 267 of the GLA protein (p.Met267Ile). The methionine residue is highly conserved and there is a small physicochemical difference between methionine and isoleucine. This variant also falls at the last nucleotide of exon 5 of the GLA coding sequence, which is part of the consensus splice site for this exon.

Comment:

The M267I mutation in the GLA gene has been reported in a single patient with Fabry disease who was hemizygous for the mutation and had a plasma alpha-Gal A activity of 0.2U/ml (Topaloglu A et al., 1999). Other mutations affecting the same residue (M267R, M267T) as well as mutations in neighboring residues (D266V, D266E, L268S) have been reported in association with Fabry disease, further supporting the functional importance of this residue and this region of the protein. Furthermore, the M267I mutation was not observed inapproximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. In summary, M267I in the GLA gene is interpreted as a disease-causing mutation. The variant is found in HCM panel(s).

Germline Functional Evidence

There is no functional evidence in ClinVar for this variation. If you have generated functional data for this variation, please consider submitting that data to ClinVar.

Comment:

Citations for germline classification of this variant

Title	Author	Journal	Year	Link
α-Galactosidase aggregation is a determinant of pharmacological chaperone efficacy on Fabry disease mutants.	Siekierska A	The Journal of biological chemistry	2012	PMID: 22773828
Aberrant 5' splice sites in human disease genes: mutation pattern, nucleotide structure and comparison of computational tools that predict their utilization.	Buratti E	Nucleic acids research	2007	PMID: 17576681
Fabry disease: 20 novel GLA mutations in 35 families.	Blaydon D	Human mutation	2001	PMID: 11668641
Twenty novel mutations in the alpha-galactosidase A gene causing Fabry disease.	Topaloglu AK	Molecular medicine (Cambridge, Mass.)	1999	PMID: 10666480
Statistical features of human exons and their flanking regions.	Zhang MQ	Human molecular genetics	1998	PMID: 9536098
http://www.egl-eurofins.com/emvclass/emvclass.php?approved_symbol=GLA	-	-	-	-

Text-mined citations for rs730880451 ...

These citations are identified by LitVar using the rs number, so they may include citations for more than one variant at this location. Please review the LitVar results carefully for your variant of interest.

Record last updated Sep 29, 2024

ClinVar Genomic variation as it relates to human health

NM_000169.3(GLA):c.801G>A (p.Met267Ile)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs730880451 ...