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NM_000169.3(GLA):c.996_999del (p.Gln333fs) AND Fabry disease

Germline classification:
Pathogenic (2 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:
RCV001389325.10

Allele description [Variation Report for NM_000169.3(GLA):c.996_999del (p.Gln333fs)]

NM_000169.3(GLA):c.996_999del (p.Gln333fs)

Genes:
RPL36A-HNRNPH2:RPL36A-HNRNPH2 readthrough [Gene - HGNC]
GLA:galactosidase alpha [Gene - OMIM - HGNC]
Variant type:
Deletion
Cytogenetic location:
Xq22.1
Genomic location:
Preferred name:
NM_000169.3(GLA):c.996_999del (p.Gln333fs)
HGVS:
  • NC_000023.11:g.101398372_101398375del
  • NG_007119.1:g.14591_14594del
  • NM_000169.3:c.996_999delMANE SELECT
  • NM_001199973.2:c.300+2915_300+2918del
  • NM_001199974.2:c.177+6550_177+6553del
  • NM_001406747.1:c.1119_1122del
  • NM_001406748.1:c.996_999del
  • NP_000160.1:p.Gln333Glufs
  • NP_000160.1:p.Gln333fs
  • NP_001393676.1:p.Gln374fs
  • NP_001393677.1:p.Arg332_Gln333insTer
  • LRG_672t1:c.994_997del
  • LRG_672:g.14591_14594del
  • LRG_672p1:p.Gln333Glufs
  • NC_000023.10:g.100653358_100653361del
  • NC_000023.10:g.100653360_100653363del
  • NM_000169.2:c.994_997delAGAC
  • NM_000169.2:c.996_999delACAG
  • NR_164783.1:n.1075_1078del
  • NR_176252.1:n.926_929del
  • NR_176253.1:n.1133_1136del
Protein change:
Q333fs
Links:
dbSNP: rs398123229
NCBI 1000 Genomes Browser:
rs398123229
Molecular consequence:
  • NM_000169.3:c.996_999del - frameshift variant - [Sequence Ontology: SO:0001589]
  • NM_001406747.1:c.1119_1122del - frameshift variant - [Sequence Ontology: SO:0001589]
  • NM_001406748.1:c.996_999del - frameshift variant - [Sequence Ontology: SO:0001589]
  • NM_001199973.2:c.300+2915_300+2918del - intron variant - [Sequence Ontology: SO:0001627]
  • NM_001199974.2:c.177+6550_177+6553del - intron variant - [Sequence Ontology: SO:0001627]
  • NR_164783.1:n.1075_1078del - non-coding transcript variant - [Sequence Ontology: SO:0001619]
  • NR_176252.1:n.926_929del - non-coding transcript variant - [Sequence Ontology: SO:0001619]
  • NR_176253.1:n.1133_1136del - non-coding transcript variant - [Sequence Ontology: SO:0001619]

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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Assertion and evidence details

Submission AccessionSubmitterReview Status
(Assertion method)
Clinical Significance
(Last evaluated)
OriginMethodCitations
SCV001590648Labcorp Genetics (formerly Invitae), Labcorp
criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))
Pathogenic
(Oct 9, 2020)
germlineclinical testing

PubMed (9)
[See all records that cite these PMIDs]

SCV002054387Genome-Nilou Lab
criteria provided, single submitter

(ACMG Guidelines, 2015)
Pathogenic
(Jul 15, 2021)
germlineclinical testing

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

Summary from all submissions

EthnicityOriginAffectedIndividualsFamiliesChromosomes testedNumber TestedFamily historyMethod
not providedgermlinenonot providednot providednot providednot providednot providedclinical testing
not providedgermlineunknownnot providednot providednot providednot providednot providedclinical testing

Citations

PubMed

Mutation analysis in patients with the typical form of Anderson-Fabry disease.

Davies JP, Winchester BG, Malcolm S.

Hum Mol Genet. 1993 Jul;2(7):1051-3. No abstract available.

PubMed [citation]
PMID:
8395937

Fabry disease: identification of 50 novel alpha-galactosidase A mutations causing the classic phenotype and three-dimensional structural analysis of 29 missense mutations.

Shabbeer J, Yasuda M, Benson SD, Desnick RJ.

Hum Genomics. 2006 Mar;2(5):297-309.

PubMed [citation]
PMID:
16595074
PMCID:
PMC3500179
See all PubMed Citations (10)

Details of each submission

From Labcorp Genetics (formerly Invitae), Labcorp, SCV001590648.4

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (9)

Description

This variant disrupts the C-terminus of the GLA protein. Other variant(s) that disrupt this region (p.Arg342*) have been determined to be pathogenic (PMID: 8395937, 16595074, 19287194, 20505683, 23980562, 26297554). This suggests that variants that disrupt this region of the protein are likely to be causative of disease. 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 disrupt the consensus splice site, but this prediction has not been confirmed by published transcriptional studies. This variant has been observed in individual(s) with Fabry disease (PMID: 12175777, 27560961). ClinVar contains an entry for this variant (Variation ID: 92575). This variant is not present in population databases (ExAC no frequency). This sequence change results in a premature translational stop signal in the GLA gene (p.Gln333Glufs*14). While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 97 amino acid(s) of the GLA protein.

#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineunknownnot providednot providednot providednot providednot providednot providednot provided

From Genome-Nilou Lab, SCV002054387.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (1)
#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlinenonot providednot providednot providednot providednot providednot providednot provided

Last Updated: Sep 29, 2024