NM_000169.3(GLA):c.427G>C (p.Ala143Pro) AND Fabry disease

Clinical significance:Pathogenic/Likely pathogenic (Last evaluated: Jan 12, 2021)

Review status:2 stars out of maximum of 4 stars

criteria provided, multiple submitters, no conflicts

Based on:
3 submissions [Details]
Record status:
current
Accession:
RCV000011516.10

Allele description [Variation Report for NM_000169.3(GLA):c.427G>C (p.Ala143Pro)]

NM_000169.3(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_000169.3(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_000169.3:c.427G>CMANE SELECT
  • NM_001199973.2:c.300+6295C>G
  • NM_001199974.2:c.177+9930C>G
  • 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
  • NM_000169.2:c.427G>C
  • NR_164783.1:n.449G>C
  • 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_001199973.2:c.300+6295C>G - intron variant - [Sequence Ontology: SO:0001627]
  • NM_001199974.2:c.177+9930C>G - intron variant - [Sequence Ontology: SO:0001627]
  • NM_000169.3:c.427G>C - missense variant - [Sequence Ontology: SO:0001583]
  • NR_164783.1:n.449G>C - non-coding transcript variant - [Sequence Ontology: SO:0001619]
Observations:
1

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
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.,

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]

SCV001361589Women's Health and Genetics/Laboratory Corporation of America, LabCorpcriteria provided, single submitter
Pathogenic
(Jan 12, 2021)
germlineclinical testing

PubMed (3)
[See all records that cite these PMIDs]

Citation Link

Summary from all submissions

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

Citations

PubMed

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

Fabry disease: renal sonographic and magnetic resonance imaging findings in affected males and carrier females with the classic and cardiac variant phenotypes.

Glass RB, Astrin KH, Norton KI, Parsons R, Eng CM, Banikazemi M, Desnick RJ.

J Comput Assist Tomogr. 2004 Mar-Apr;28(2):158-68.

PubMed [citation]
PMID:
15091117
See all PubMed Citations (9)

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 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 o f 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. Computation al analyses (biochemical amino acid properties, conservation, AlignGVGD, PolyPhe n2, and SIFT) do not provide strong support for or against an impact to the prot ein. Finally, another variant at this position (Arg143Thr) has been reported in multiple individuals with Fabry disease, segregated with disease (Spada 2006, Te rryn 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, tho ugh additional studies are required to fully establish its clinical significance .

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

From Women's Health and Genetics/Laboratory Corporation of America, LabCorp, SCV001361589.2

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (3)

Description

Variant summary: GLA c.427G>C (p.Ala143Pro) results in a non-conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 183467 control chromosomes (gnomAD). c.427G>C has been reported in the literature in at least an individual affected with Classic Fabry Disease (example: Eng_1994). These data indicate that the variant is likely to be associated with disease. Enzymatic activity from patient derived samples as well as in vitro studies reveal that the variant resulted in reduced or no enzymatic activity (Altarescu_2001, Lukas_2013). One other ClinVar submitter (evaluation after 2014) cite the variant as pathogenic. 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

Last Updated: Dec 4, 2021

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