NM_000169.2(GLA):c.427G>C (p.Ala143Pro) AND Fabry disease

Clinical significance:Conflicting interpretations of pathogenicity, Likely pathogenic(1);Pathogenic(2) (Last evaluated: Jan 17, 2014)

Review status:1 star out of maximum of 4 stars

criteria provided, conflicting interpretations

Based on:
3 submissions [Details]
Record status:
current
Accession:
RCV000011516.6

Allele description

NM_000169.2(GLA):c.427G>C (p.Ala143Pro)

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_000169.2(GLA):c.427G>C (p.Ala143Pro)
Other names:
p.A143P:GCA>CCA
HGVS:
  • NC_000023.11:g.101401752C>G
  • NG_007119.1:g.11212G>C
  • NM_000169.2:c.427G>C
  • NP_000160.1:p.Ala143Pro
  • LRG_672t1:c.427G>C
  • LRG_672:g.11212G>C
  • LRG_672p1:p.Ala143Pro
  • NC_000023.10:g.100656740C>G
  • P06280:p.Ala143Pro
Protein change:
A143P; ALA143PRO
Links:
UniProtKB: P06280#VAR_000453; OMIM: 300644.0057; dbSNP: rs104894845
NCBI 1000 Genomes Browser:
rs104894845
Molecular consequence:
  • NM_000169.2:c.427G>C - missense variant - [Sequence Ontology: SO:0001583]
Observations:
1

Condition(s)

Name:
Fabry disease
Synonyms:
Angiokeratoma corporis diffusum; Fabry's disease; Fabry syndrome
Identifiers:
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
SCV000031748OMIMno assertion criteria providedPathogenic
(Mar 1, 2002)
germlineliterature only

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

Kopp, J. B. Personal Communication. 2002. Bethesda, Md.,

SCV000110120EGL Genetic Diagnostics,Eurofins Clinical Diagnosticscriteria provided, single submitter
Pathogenic
(Nov 13, 2013)
germlineclinical testing

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

Citation Link,

SCV000205984Laboratory for Molecular Medicine,Partners HealthCare Personalized Medicinecriteria provided, single submitter
Likely pathogenic
(Jan 17, 2014)
germlineclinical testing

PubMed (7)
[See all records that cite these PMIDs]

Summary from all submissions

EthnicityOriginAffectedIndividualsFamiliesChromosomes testedNumber TestedFamily historyMethod
not providedgermlineunknown3not providednot providednot providednot providedclinical testing
not providedgermlinenot provided11not providednot providednot providedliterature only, clinical testing

Citations

PubMed

Effect of ivacaftor on CFTR forms with missense mutations associated with defects in protein processing or function.

Van Goor F, Yu H, Burton B, Hoffman BJ.

J Cyst Fibros. 2014 Jan;13(1):29-36. doi: 10.1016/j.jcf.2013.06.008. Epub 2013 Jul 23.

PubMed [citation]
PMID:
23891399

Natural history of Fabry renal disease: influence of alpha-galactosidase A activity and genetic mutations on clinical course.

Branton MH, Schiffmann R, Sabnis SG, Murray GJ, Quirk JM, Altarescu G, Goldfarb L, Brady RO, Balow JE, Austin Iii HA, Kopp JB.

Medicine (Baltimore). 2002 Mar;81(2):122-38. No abstract available.

PubMed [citation]
PMID:
11889412
See all PubMed Citations (8)

Details of each submission

From OMIM, SCV000031748.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedliterature only PubMed (1)

Description

In 4 unrelated patients of Nova Scotian ancestry with Fabry disease (301500), Branton et al. (2002) found an ala143-to-pro (A143P) missense mutation in exon 3 of the GLA gene. Three of the patients were French Acadian; the fourth had a Greek surname but may also have been of French Acadian ancestry (Kopp, 2002).

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

From EGL Genetic Diagnostics,Eurofins Clinical Diagnostics, SCV000110120.7

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not provided3not providednot providedclinical testing PubMed (1)
#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineunknownnot providednot providednot provided3not providednot providednot provided

From Laboratory for Molecular Medicine,Partners HealthCare Personalized Medicine, SCV000205984.4

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not provided1not providednot providedclinical testing PubMed (7)

Description

The Arg143Pro variant in GLA as been reported in 6 males with Fabry disease, 5 of whom were of Nova Scotian ancestry (Eng 1994, Branton 2002, Glass 2004). For 2 of them, absence of alpha-galatosidase enzyme activity was reported (Branton 2002). This variant was not identified in large population studies. Computational analyses (biochemical amino acid properties, conservation, AlignGVGD, PolyPhen2, and SIFT) do not provide strong support for or against an impact to the protein. Finally, another variant at this position (Arg143Thr) has been reported in multiple individuals with Fabry disease, segregated with disease (Spada 2006, Terryn 2008), and is considered disease-causing, further supporting that a change at this position is not tolerated. In summary, the presence in multiple affected individuals, absence from large populations, and presence of another variant at the same position all support that this variant is likely to be pathogenic, though additional studies are required to fully establish its clinical significance.

#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlinenot providednot providednot providednot provided1not provided1not provided

Last Updated: Apr 27, 2018