NM_000169.3(GLA):c.1094dup (p.Tyr365Ter) AND Fabry disease

Germline classification:: Pathogenic (1 submission)
Last evaluated:: Sep 27, 2022
Review status:: 1 star out of maximum of 4 stars
criteria provided, single submitter

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:: RCV002825652.3

Allele description [Variation Report for NM_000169.3(GLA):c.1094dup (p.Tyr365Ter)]

NM_000169.3(GLA):c.1094dup (p.Tyr365Ter)

Genes:

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

Variant type:

Duplication

Cytogenetic location:

Xq22.1

Genomic location:

Preferred name:

NM_000169.3(GLA):c.1094dup (p.Tyr365Ter)

HGVS:

NC_000023.11:g.101398005dup
NG_007119.1:g.14959dup
NM_000169.3:c.1094dupMANE SELECT
NM_001199973.2:c.300+2548dup
NM_001199974.2:c.177+6183dup
NM_001406747.1:c.1217dup
NP_000160.1:p.Tyr365Ter
NP_000160.1:p.Tyr365Terfs
NP_001393676.1:p.Tyr406Terfs
LRG_672t1:c.1094dup
LRG_672:g.14959dup
LRG_672p1:p.Tyr365Terfs
NC_000023.10:g.100652992_100652993insT
NC_000023.10:g.100652993dup
NM_000169.2:c.1094dup
NR_164783.1:n.1173dup
NR_176252.1:n.1024dup
NR_176253.1:n.1231dup

Protein change:

Y365*

Molecular consequence:

NM_001406747.1:c.1217dup - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001199973.2:c.300+2548dup - intron variant - [Sequence Ontology: SO:0001627]
NM_001199974.2:c.177+6183dup - intron variant - [Sequence Ontology: SO:0001627]
NR_164783.1:n.1173dup - non-coding transcript variant - [Sequence Ontology: SO:0001619]
NM_000169.3:c.1094dup - nonsense - [Sequence Ontology: SO:0001587]
NM_001406747.1:c.1217dup - 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
SCV003206441	Invitae	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Sep 27, 2022)	germline	clinical testing	PubMed (6) [See all records that cite these PMIDs] 11668641, 12428061, 21598360, 30988410, 31996269, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV003206441

Invitae

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Pathogenic
(Sep 27, 2022)

germline

clinical testing

PubMed (6)
[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

Citations

PubMed

Fabry disease: 20 novel GLA mutations in 35 families.

Blaydon D, Hill J, Winchester B.

Hum Mutat. 2001 Nov;18(5):459.

PubMed [citation]

PMID:: 11668641

Fabry disease: twenty novel alpha-galactosidase A mutations and genotype-phenotype correlations in classical and variant phenotypes.

Germain DP, Shabbeer J, Cotigny S, Desnick RJ.

Mol Med. 2002 Jun;8(6):306-12.

PubMed [citation]

PMID:: 12428061
PMCID:: PMC2039995

See all PubMed Citations (6)

Details of each submission

From Invitae, SCV003206441.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (6)

Description

For these reasons, this variant has been classified as Pathogenic. This variant disrupts a region of the GLA protein in which other variant(s) (p.Pro409Ser) have been determined to be pathogenic (PMID: 11668641, 12428061, 21598360; Invitae). This suggests that this is a clinically significant region of the protein, and that variants that disrupt it are likely to be disease-causing. This premature translational stop signal has been observed in individuals with Fabry disease (PMID: 30988410, 31996269). This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Tyr365*) in the GLA gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 65 amino acid(s) of the GLA protein.

#	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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