NC_000023.11:g.101398566_101398569del AND Fabry disease

Germline classification:
Pathogenic (2 submissions)
Last evaluated:
May 24, 2023
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:
RCV001192398.9

Allele description [Variation Report for NC_000023.11:g.101398566_101398569del]

NC_000023.11:g.101398566_101398569del

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:
NC_000023.11:g.101398566_101398569del
HGVS:
  • NC_000023.11:g.101398566_101398569del
  • NG_007119.1:g.14398_14401del
  • NM_001199973.2:c.300+3109_300+3112del
  • NM_001199974.2:c.177+6744_177+6747del
  • LRG_672:g.14398_14401del
  • NC_000023.10:g.100653551_100653554del
  • NC_000023.10:g.100653554_100653557del
  • p.L268X
Links:
dbSNP: rs869312426
NCBI 1000 Genomes Browser:
rs869312426
Molecular consequence:
  • NM_001199973.2:c.300+3109_300+3112del - intron variant - [Sequence Ontology: SO:0001627]
  • NM_001199974.2:c.177+6744_177+6747del - intron variant - [Sequence Ontology: SO:0001627]
Functional consequence:
effect on protein activity [Variation Ontology: 0053]

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

Help
Submission AccessionSubmitterReview Status
(Assertion method)		Clinical Significance
(Last evaluated)		OriginMethodCitations
SCV001360484Women's Health and Genetics/Laboratory Corporation of America, LabCorp
criteria provided, single submitter

(LabCorp Variant Classification Summary - May 2015)		Pathogenic
(May 29, 2019) 		germlineclinical testing

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

Citation Link,

SCV001587058Labcorp Genetics (formerly Invitae), Labcorp
criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))		Pathogenic
(May 24, 2023) 		germlineclinical testing

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

Help

Summary from all submissions

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

Citations

PubMed

Female Fabry disease patients and X-chromosome inactivation.

Juchniewicz P, Kloska A, Tylki-Szymańska A, Jakóbkiewicz-Banecka J, Węgrzyn G, Moskot M, Gabig-Cimińska M, Piotrowska E.

Gene. 2018 Jan 30;641:259-264. doi: 10.1016/j.gene.2017.10.064. Epub 2017 Oct 25.

PubMed [citation]
PMID:
29079200

Characterization of early disease status in treatment-naive male paediatric patients with Fabry disease enrolled in a randomized clinical trial.

Wijburg FA, Bénichou B, Bichet DG, Clarke LA, Dostalova G, Fainboim A, Fellgiebel A, Forcelini C, An Haack K, Hopkin RJ, Mauer M, Najafian B, Scott CR, Shankar SP, Thurberg BL, Tøndel C, Tylki-Szymańska A, Ramaswami U.

PLoS One. 2015;10(5):e0124987. doi: 10.1371/journal.pone.0124987.

PubMed [citation]
PMID:
25955246
PMCID:
PMC4425695
See all PubMed Citations (6)

Details of each submission

From Women's Health and Genetics/Laboratory Corporation of America, LabCorp, SCV001360484.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (4)

Description

Variant summary: GLA c.803_806delTAGT (p.Leu268X) 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 (eg. c.901C>T (p.Arg301X), c.1021G>T(p.Glu341X)). The variant was absent in 182745 control chromosomes (gnomAD) but has been reported in the literature in male patients affected with Fabry Disease as well as in symptomatic heterozygous females (Juchniewicz_2018, Wijburg_2014, Lee_2000). Taken together, these data indicate that the variant is very likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. No submitters have provided clinical-significance assessments for this variant to ClinVar after 2014. Based on the evidence outlined above, the variant was classified as pathogenic.

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

From Labcorp Genetics (formerly Invitae), Labcorp, SCV001587058.4

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (4)

Description

This sequence change creates a premature translational stop signal (p.Leu268*) 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). This variant is not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individual(s) with Fabry disease (PMID: 11076046, 12175777). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 1323012). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic.

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

Last Updated: Oct 8, 2024