NM_000169.3(GLA):c.485G>A (p.Trp162Ter) AND Fabry disease

Germline classification:: Pathogenic (3 submissions)
Last evaluated:: Nov 29, 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:: RCV000176999.9

Allele description [Variation Report for NM_000169.3(GLA):c.485G>A (p.Trp162Ter)]

NM_000169.3(GLA):c.485G>A (p.Trp162Ter)

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.485G>A (p.Trp162Ter)

HGVS:

NC_000023.11:g.101401694C>T
NG_007119.1:g.11270G>A
NM_000169.3:c.485G>AMANE SELECT
NM_001199973.2:c.300+6237C>T
NM_001199974.2:c.177+9872C>T
NP_000160.1:p.Trp162Ter
NP_000160.1:p.Trp162Ter
LRG_672t1:c.485G>A
LRG_672:g.11270G>A
LRG_672p1:p.Trp162Ter
NC_000023.10:g.100656682C>T
NM_000169.2:c.485G>A
NR_164783.1:n.507G>A

Protein change:

W162*

Links:

dbSNP: rs727504350

NCBI 1000 Genomes Browser:

rs727504350

Molecular consequence:

NM_001199973.2:c.300+6237C>T - intron variant - [Sequence Ontology: SO:0001627]
NM_001199974.2:c.177+9872C>T - intron variant - [Sequence Ontology: SO:0001627]
NR_164783.1:n.507G>A - non-coding transcript variant - [Sequence Ontology: SO:0001619]
NM_000169.3:c.485G>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
SCV000695741	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015)	Pathogenic (Dec 14, 2016)	germline	clinical testing	PubMed (4) [See all records that cite these PMIDs] 11668641, 15776423, 26415523, 10649504 LabCorp Variant Classification Summary - May 2015.docx, Citation Link,
SCV000935550	Invitae	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Nov 29, 2021)	germline	clinical testing	PubMed (5) [See all records that cite these PMIDs] 10649504, 11668641, 10666480, 12175777, 28492532
SCV002054431	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]

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000695741

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

criteria provided, single submitter

(LabCorp Variant Classification Summary - May 2015)

Pathogenic
(Dec 14, 2016)

germline

clinical testing

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

LabCorp Variant Classification Summary - May 2015.docx,

Citation Link,

SCV000935550

Invitae

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Pathogenic
(Nov 29, 2021)

germline

clinical testing

PubMed (5)
[See all records that cite these PMIDs]

SCV002054431

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]

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

Thirty-four novel mutations of the GLA gene in 121 patients with Fabry disease.

Schäfer E, Baron K, Widmer U, Deegan P, Neumann HP, Sunder-Plassmann G, Johansson JO, Whybra C, Ries M, Pastores GM, Mehta A, Beck M, Gal A.

Hum Mutat. 2005 Apr;25(4):412.

PubMed [citation]

PMID:: 15776423

Functional and Clinical Consequences of Novel α-Galactosidase A Mutations in Fabry Disease.

Lukas J, Scalia S, Eichler S, Pockrandt AM, Dehn N, Cozma C, Giese AK, Rolfs A.

Hum Mutat. 2016 Jan;37(1):43-51. doi: 10.1002/humu.22910. Epub 2015 Oct 27.

PubMed [citation]

PMID:: 26415523

See all PubMed Citations (8)

Details of each submission

From Women's Health and Genetics/Laboratory Corporation of America, LabCorp, SCV000695741.1

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

Description

Variant summary: The GLA c.485G>A (p.Trp162X) variant results in a premature termination codon, predicted to cause a truncated or absent GLA protein due to nonsense mediated decay, which are commonly known mechanisms for disease. The variant of interest was not observed in controls (ExAC, 1000 Gs, or ESP) and has been reported in multiple affected individuals including one family that female individuals in the family carrying the variant showed mild features including low levels of GLA activity. In addition, males carrying the variant of interest showed no GLA activity. In addition, a clinical diagnostic laboratory cites the variant as "pathogenic." Therefore, the variant of interest has been 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 Invitae, SCV000935550.4

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (5)

Description

For these reasons, this variant has been classified as Pathogenic. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. ClinVar contains an entry for this variant (Variation ID: 196226). This premature translational stop signal has been observed in individuals with Fabry disease (PMID: 10649504, 11668641). This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Trp162*) 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

From Genome-Nilou Lab, SCV002054431.1

#	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

Last Updated: Apr 15, 2024

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