VCV002584496.2 - ClinVar

NM_000169.3(GLA):c.1133G>A (p.Cys378Tyr)

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.

(2)

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.

Likely 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.1133G>A (p.Cys378Tyr)

Variation ID: 2584496 Accession: VCV002584496.2

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: Xq22.1 X: 101397966 (GRCh38) [ NCBI UCSC ] X: 100652954 (GRCh37) [ 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	Oct 21, 2023	Feb 14, 2024	Nov 24, 2022

HGVS

Nucleotide	Protein	Molecular consequence
NM_000169.3:c.1133G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_000160.1:p.Cys378Tyr	missense
NM_001199973.2:c.300+2509C>T		intron variant
NM_001199974.2:c.177+6144C>T		intron variant
NM_001406747.1:c.1256G>A	NP_001393676.1:p.Cys419Tyr	missense
NR_164783.1:n.1212G>A		non-coding transcript variant
NR_176252.1:n.1063G>A		non-coding transcript variant
NR_176253.1:n.1270G>A		non-coding transcript variant
NC_000023.11:g.101397966C>T
NC_000023.10:g.100652954C>T
NG_007119.1:g.14998G>A
LRG_672:g.14998G>A
LRG_672t1:c.1133G>A	LRG_672p1:p.Cys378Tyr

... more HGVS ... less HGVS

Protein change

C378Y, C419Y

Other names

Canonical SPDI

NC_000023.11:101397965: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

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	-	1295

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.
Fabry disease	Likely pathogenic (2)	criteria provided, multiple submitters, no conflicts	Nov 24, 2022	RCV003335936.3

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.
Likely pathogenic (-)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	FABRY DISEASE Affected status: yes Allele origin: germline	Rady Children's Institute for Genomic Medicine, Rady Children's Hospital San Diego Accession: SCV004046287.1 First in ClinVar: Oct 21, 2023 Last updated: Oct 21, 2023	Comment: This variant has been previously reported as a heterozygous and hemizygous changes in patients with classical Fabry disease (PMID: 12920095, 10666480). It is absent from … (more) This variant has been previously reported as a heterozygous and hemizygous changes in patients with classical Fabry disease (PMID: 12920095, 10666480). It is absent from the gnomAD population database and thus is presumed to be rare. The c.1133G>A (p.Cys378Tyr) variant affects a highly conserved amino acid and is predicted by multiple in silico tools to have a deleterious effect on protein function. Based on the available evidence, the c.1133G>A (p.Cys378Tyr) variant is classified as Likely Pathogenic. (less)
Likely pathogenic (Nov 24, 2022)	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: SCV004299620.1 First in ClinVar: Feb 14, 2024 Last updated: Feb 14, 2024	Publications: PubMed (5) PubMed: 23935525‚ 30386727‚ 10666480‚ 12920095‚ 26047621 Comment: In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has … (more) In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. This variant disrupts the p.Cys378 amino acid residue in GLA. Other variant(s) that disrupt this residue have been observed in individuals with GLA-related conditions (PMID: 23935525, 30386727), which suggests that this may be a clinically significant amino acid residue. 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 GLA protein function. This missense change has been observed in individual(s) with Fabry disease (PMID: 10666480, 12920095, 26047621). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces cysteine, which is neutral and slightly polar, with tyrosine, which is neutral and polar, at codon 378 of the GLA protein (p.Cys378Tyr). (less)

Comment:

This variant has been previously reported as a heterozygous and hemizygous changes in patients with classical Fabry disease (PMID: 12920095, 10666480). It is absent from the gnomAD population database and thus is presumed to be rare. The c.1133G>A (p.Cys378Tyr) variant affects a highly conserved amino acid and is predicted by multiple in silico tools to have a deleterious effect on protein function. Based on the available evidence, the c.1133G>A (p.Cys378Tyr) variant is classified as Likely Pathogenic.

Comment:

In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. This variant disrupts the p.Cys378 amino acid residue in GLA. Other variant(s) that disrupt this residue have been observed in individuals with GLA-related conditions (PMID: 23935525, 30386727), which suggests that this may be a clinically significant amino acid residue. 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 GLA protein function. This missense change has been observed in individual(s) with Fabry disease (PMID: 10666480, 12920095, 26047621). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces cysteine, which is neutral and slightly polar, with tyrosine, which is neutral and polar, at codon 378 of the GLA protein (p.Cys378Tyr).

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
Fabry disease in a Japanese population-molecular and biochemical characteristics.	Sakuraba H	Molecular genetics and metabolism reports	2018	PMID: 30386727
Pathology and function of conduction tissue in Fabry disease cardiomyopathy.	Frustaci A	Circulation. Arrhythmia and electrophysiology	2015	PMID: 26047621
Functional characterisation of alpha-galactosidase a mutations as a basis for a new classification system in fabry disease.	Lukas J	PLoS genetics	2013	PMID: 23935525
Fabry disease: molecular studies in Italian patients and X inactivation analysis in manifesting carriers.	Morrone A	Journal of medical genetics	2003	PMID: 12920095
Twenty novel mutations in the alpha-galactosidase A gene causing Fabry disease.	Topaloglu AK	Molecular medicine (Cambridge, Mass.)	1999	PMID: 10666480

Text-mined citations for this variant ...

Record last updated Sep 30, 2024

ClinVar Genomic variation as it relates to human health

NM_000169.3(GLA):c.1133G>A (p.Cys378Tyr)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for this variant ...