VCV000092570.21 - ClinVar

NM_000169.3(GLA):c.901C>T (p.Arg301Ter)

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.

(7)

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.901C>T (p.Arg301Ter)

Variation ID: 92570 Accession: VCV000092570.21

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: Xq22.1 X: 101398468 (GRCh38) [ NCBI UCSC ] X: 100653456 (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	May 29, 2016	Feb 14, 2024	Jul 28, 2023

HGVS

Nucleotide	Protein	Molecular consequence
NM_000169.3:c.901C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_000160.1:p.Arg301Ter	nonsense
NM_001199973.2:c.300+3011G>A		intron variant
NM_001199974.2:c.177+6646G>A		intron variant
NM_001406747.1:c.1024C>T	NP_001393676.1:p.Arg342Ter	nonsense
NM_001406748.1:c.901C>T	NP_001393677.1:p.Arg301Ter	nonsense
NR_164783.1:n.980C>T		non-coding transcript variant
NR_176252.1:n.831C>T		non-coding transcript variant
NR_176253.1:n.1038C>T		non-coding transcript variant
NC_000023.11:g.101398468G>A
NC_000023.10:g.100653456G>A
NG_007119.1:g.14496C>T
LRG_672:g.14496C>T
LRG_672t1:c.901C>T	LRG_672p1:p.Arg301Ter

... more HGVS ... less HGVS

Protein change

R301*, R342*

Other names

NP_000160.1:p.Arg301*
p.R301*:CGA>TGA

Canonical SPDI

NC_000023.11:101398467:G:A

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

effect on protein activity; Variation Ontology [ VariO:0053]

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: CA022184 dbSNP: rs398123224 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 (3)	criteria provided, multiple submitters, no conflicts	Dec 14, 2022	RCV000157879.13
Fabry disease	Pathogenic (4)	criteria provided, multiple submitters, no conflicts	Jul 28, 2023	RCV000781418.13

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 (Dec 14, 2022)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	not provided Affected status: unknown Allele origin: germline	Revvity Omics, Revvity Accession: SCV002024294.3 First in ClinVar: Nov 29, 2021 Last updated: Feb 04, 2024
Pathogenic (Jun 10, 2021)	criteria provided, single submitter (GeneDx Variant Classification Process June 2021) Method: clinical testing	Not Provided Affected status: yes Allele origin: germline	GeneDx Accession: SCV000207810.13 First in ClinVar: Feb 24, 2015 Last updated: Apr 17, 2019	Comment: Not observed at significant frequency in large population cohorts (Lek et al., 2016); Nonsense variant predicted to result in protein truncation or nonsense-mediated decay in … (more) Not observed at significant frequency in large population cohorts (Lek et al., 2016); Nonsense variant predicted to result in protein truncation or nonsense-mediated decay in a gene for which loss-of-function is a known mechanism of disease; This variant is associated with the following publications: (PMID: 15713906, 15776423, 27560961, 28679849, 27535533, 25525159, 15806320, 11668641, 12428061, 8996967, 27899143, 27156739, 26602202, 18651238, 23935525, 28090261, 28728877, 27773586, 31996269, 7531540) (less)
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: SCV002054394.1 First in ClinVar: Jan 12, 2022 Last updated: Jan 12, 2022
Pathogenic (Mar 05, 2015)	criteria provided, single submitter (EGL Classification Definitions 2015) Method: clinical testing	not provided Affected status: unknown Allele origin: germline	Eurofins Ntd Llc (ga) Accession: SCV000110141.8 First in ClinVar: Jan 17, 2014 Last updated: Dec 15, 2018	Publications: PubMed (1) PubMed: 7531540 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: 13 Sex: mixed
Pathogenic (Jul 03, 2019)	criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015) Method: clinical testing	Fabry disease Affected status: unknown Allele origin: germline	Women's Health and Genetics/Laboratory Corporation of America, LabCorp Accession: SCV000919436.2 First in ClinVar: Jun 02, 2019 Last updated: Nov 08, 2019	Publications: PubMed (7) PubMed: 15776423‚ 15713906‚ 23935525‚ 18698230‚ 24236025‚ 11668641‚ 23566439 Comment: Variant summary: GLA c.901C>T (p.Arg301X) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein … (more) Variant summary: GLA c.901C>T (p.Arg301X) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. Truncations downstream of this position have been classified as pathogenic by our laboratory. The variant was absent in 183457 control chromosomes (gnomAD). c.901C>T has been reported in the literature in multiple individuals affected with Fabry Disease (Bowman_2013, Lukas_2013, Schafer_2005, Ries_2005, Blaydon_2001, Nakano_2013, Shin_2008). These data indicate that the variant is very likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function. The most pronounced variant effect results in <10% of normal activity (Shin_2008, Ries_2005). Two ClinVar submissions (evaluation after 2014) cite the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. (less)
Pathogenic (Jul 28, 2023)	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: SCV001590650.4 First in ClinVar: May 10, 2021 Last updated: Feb 14, 2024	Publications: PubMed (4) PubMed: 7531540‚ 28728877‚ 10666480‚ 12175777 Comment: This premature translational stop signal has been observed in individuals with Fabry disease (PMID: 7531540, 28728877). ClinVar contains an entry for this variant (Variation ID: … (more) This premature translational stop signal has been observed in individuals with Fabry disease (PMID: 7531540, 28728877). ClinVar contains an entry for this variant (Variation ID: 92570). For these reasons, this variant has been classified as Pathogenic. This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Arg301*) in the GLA gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in GLA are known to be pathogenic (PMID: 10666480, 12175777). (less)
Pathogenic (Nov 02, 2023)	no assertion criteria provided Method: clinical testing	Fabry disease Affected status: yes Allele origin: germline	Zotz-Klimas Genetics Lab, MVZ Zotz Klimas Accession: SCV004101116.1 First in ClinVar: Nov 11, 2023 Last updated: Nov 11, 2023

Comment:

Not observed at significant frequency in large population cohorts (Lek et al., 2016); Nonsense variant predicted to result in protein truncation or nonsense-mediated decay in a gene for which loss-of-function is a known mechanism of disease; This variant is associated with the following publications: (PMID: 15713906, 15776423, 27560961, 28679849, 27535533, 25525159, 15806320, 11668641, 12428061, 8996967, 27899143, 27156739, 26602202, 18651238, 23935525, 28090261, 28728877, 27773586, 31996269, 7531540)

Comment:

Variant summary: GLA c.901C>T (p.Arg301X) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. Truncations downstream of this position have been classified as pathogenic by our laboratory. The variant was absent in 183457 control chromosomes (gnomAD). c.901C>T has been reported in the literature in multiple individuals affected with Fabry Disease (Bowman_2013, Lukas_2013, Schafer_2005, Ries_2005, Blaydon_2001, Nakano_2013, Shin_2008). These data indicate that the variant is very likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function. The most pronounced variant effect results in <10% of normal activity (Shin_2008, Ries_2005). Two ClinVar submissions (evaluation after 2014) cite the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.

Comment:

This premature translational stop signal has been observed in individuals with Fabry disease (PMID: 7531540, 28728877). ClinVar contains an entry for this variant (Variation ID: 92570). For these reasons, this variant has been classified as Pathogenic. This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Arg301*) in the GLA gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in GLA are known to be pathogenic (PMID: 10666480, 12175777).

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
Genotype, phenotype and disease severity reflected by serum LysoGb3 levels in patients with Fabry disease.	Nowak A	Molecular genetics and metabolism	2018	PMID: 28728877
Development of a highly sensitive immuno-PCR assay for the measurement of α-galactosidase A protein levels in serum and plasma.	Nakano S	PloS one	2013	PMID: 24236025
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 patients' experiences with the timing of diagnosis relevant for the discussion on newborn screening.	Bouwman MG	Molecular genetics and metabolism	2013	PMID: 23566439
Prediction of response of mutated alpha-galactosidase A to a pharmacological chaperone.	Shin SH	Pharmacogenetics and genomics	2008	PMID: 18698230
Thirty-four novel mutations of the GLA gene in 121 patients with Fabry disease.	Schäfer E	Human mutation	2005	PMID: 15776423
Pediatric Fabry disease.	Ries M	Pediatrics	2005	PMID: 15713906
Fabry disease: 45 novel mutations in the alpha-galactosidase A gene causing the classical phenotype.	Shabbeer J	Molecular genetics and metabolism	2002	PMID: 12175777
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
Fabry disease: twenty-three mutations including sense and antisense CpG alterations and identification of a deletional hot-spot in the alpha-galactosidase A gene.	Eng CM	Human molecular genetics	1994	PMID: 7531540
http://www.egl-eurofins.com/emvclass/emvclass.php?approved_symbol=GLA	-	-	-	-
click to load more click to collapse

Text-mined citations for rs398123224 ...

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.901C>T (p.Arg301Ter)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs398123224 ...