NM_000169.3(GLA):c.734G>A (p.Trp245Ter) AND Fabry disease

Germline classification:: Pathogenic (3 submissions)
Last evaluated:: Jul 15, 2021
Review status:: 2 stars out of maximum of 4 stars
criteria provided, multiple submitters, no conflicts

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:: RCV001193671.9

Allele description [Variation Report for NM_000169.3(GLA):c.734G>A (p.Trp245Ter)]

NM_000169.3(GLA):c.734G>A (p.Trp245Ter)

Genes:

RPL36A-HNRNPH2:RPL36A-HNRNPH2 readthrough [Gene - HGNC]
GLA:galactosidase alpha [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

Xq22.1

Genomic location:

Preferred name:

NM_000169.3(GLA):c.734G>A (p.Trp245Ter)

Other names:

NP_000160.1:p.Trp245*

HGVS:

NC_000023.11:g.101398852C>T
NG_007119.1:g.14112G>A
NM_000169.3:c.734G>AMANE SELECT
NM_001199973.2:c.300+3395C>T
NM_001199974.2:c.177+7030C>T
NP_000160.1:p.Trp245Ter
NP_000160.1:p.Trp245Ter
LRG_672t1:c.734G>A
LRG_672:g.14112G>A
LRG_672p1:p.Trp245Ter
NC_000023.10:g.100653840C>T
NM_000169.2:c.734G>A
NR_164783.1:n.813G>A

Protein change:

W245*

Links:

dbSNP: rs398123220

NCBI 1000 Genomes Browser:

rs398123220

Molecular consequence:

NM_001199973.2:c.300+3395C>T - intron variant - [Sequence Ontology: SO:0001627]
NM_001199974.2:c.177+7030C>T - intron variant - [Sequence Ontology: SO:0001627]
NR_164783.1:n.813G>A - non-coding transcript variant - [Sequence Ontology: SO:0001619]
NM_000169.3:c.734G>A - nonsense - [Sequence Ontology: SO:0001587]

Condition(s)

Name:: Fabry disease
Synonyms:: Angiokeratoma, diffuse; Anderson-Fabry disease; Hereditary dystopic lipidosis; See all synonyms [MedGen]
Identifiers:: MONDO: MONDO:0010526; MedGen: C0002986; Orphanet: 324; OMIM: 301500; Human Phenotype Ontology: HP:0001071

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV001362667	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015)	Pathogenic (Oct 22, 2019)	germline	clinical testing	PubMed (4) [See all records that cite these PMIDs] 12428061, 25511234, 30386727, 27896103 Citation Link,
SCV002054414	Genome-Nilou Lab	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Jul 15, 2021)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV002139142	Invitae	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Apr 8, 2021)	germline	clinical testing	PubMed (4) [See all records that cite these PMIDs] 12428061, 10666480, 12175777, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV001362667

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

criteria provided, single submitter

(LabCorp Variant Classification Summary - May 2015)

Pathogenic
(Oct 22, 2019)

germline

clinical testing

PubMed (4)
[See all records that cite these PMIDs]

Citation Link,

SCV002054414

Genome-Nilou Lab

criteria provided, single submitter

(ACMG Guidelines, 2015)

Pathogenic
(Jul 15, 2021)

germline

clinical testing

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

SCV002139142

Invitae

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Pathogenic
(Apr 8, 2021)

germline

clinical testing

PubMed (4)
[See all records that cite these PMIDs]

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing
not provided	germline	no	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

Raynaud's phenomenon associated with Fabry disease.

Germain DP, Atanasiu OI, Akrout-Marouene J, Benistan K.

J Inherit Metab Dis. 2015 Mar;38(2):367-8. doi: 10.1007/s10545-014-9799-z. Epub 2014 Dec 16. No abstract available.

PubMed [citation]

PMID:: 25511234

Fabry disease in a Japanese population-molecular and biochemical characteristics.

Sakuraba H, Tsukimura T, Togawa T, Tanaka T, Ohtsuka T, Sato A, Shiga T, Saito S, Ohno K.

Mol Genet Metab Rep. 2018 Dec;17:73-79. doi: 10.1016/j.ymgmr.2018.10.004.

PubMed [citation]

PMID:: 30386727
PMCID:: PMC6205336

See all PubMed Citations (8)

Details of each submission

From Women's Health and Genetics/Laboratory Corporation of America, LabCorp, SCV001362667.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (4)

Description

Variant summary: GLA c.734G>A (p.Trp245X) 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 183472 control chromosomes. c.734G>A has been reported in the literature in individuals affected with Fabry Disease (Germain_2015, Germain_2002, Sakurab_2018, Tsukimura_2014). These data indicate that the variant may be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. A ClinVar submission (evaluation after 2014) cites the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Genome-Nilou Lab, SCV002054414.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (1)

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	no	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Invitae, SCV002139142.3

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (4)

Description

For these reasons, this variant has been classified as Pathogenic. This variant has been observed in individual(s) with Fabry disease (PMID: 12428061). ClinVar contains an entry for this variant (Variation ID: 92564). This variant is not present in population databases (ExAC no frequency). This sequence change creates a premature translational stop signal (p.Trp245*) 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).

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

Last Updated: Apr 15, 2024

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