NM_000027.4(AGA):c.436T>G (p.Leu146Val) AND not provided

Clinical significance:Conflicting interpretations of pathogenicity, Likely pathogenic(1);Uncertain significance(1) (Last evaluated: Aug 29, 2017)

Review status:1 star out of maximum of 4 stars

criteria provided, conflicting interpretations

Based on:
3 submissions [Details]
Record status:
current
Accession:
RCV000489452.4

Allele description [Variation Report for NM_000027.4(AGA):c.436T>G (p.Leu146Val)]

NM_000027.4(AGA):c.436T>G (p.Leu146Val)

Gene:
AGA:aspartylglucosaminidase [Gene - OMIM - HGNC]
Variant type:
single nucleotide variant
Cytogenetic location:
4q34.3
Genomic location:
Preferred name:
NM_000027.4(AGA):c.436T>G (p.Leu146Val)
HGVS:
  • NC_000004.12:g.177438816A>C
  • NG_011845.2:g.8688T>G
  • NM_000027.4:c.436T>GMANE SELECT
  • NM_001171988.1:c.436T>G
  • NP_000018.2:p.Leu146Val
  • NP_001165459.1:p.Leu146Val
  • NC_000004.11:g.178359970A>C
  • NM_000027.3:c.436T>G
  • NR_033655.1:n.564T>G
Protein change:
L146V
Links:
dbSNP: rs146381591
NCBI 1000 Genomes Browser:
rs146381591
Molecular consequence:
  • NM_000027.4:c.436T>G - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001171988.1:c.436T>G - missense variant - [Sequence Ontology: SO:0001583]
  • NR_033655.1:n.564T>G - non-coding transcript variant - [Sequence Ontology: SO:0001619]
Observations:
1

Condition(s)

Identifiers:
MedGen: CN517202

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Assertion and evidence details

Submission AccessionSubmitterReview Status
(Assertion method)
Clinical Significance
(Last evaluated)
OriginMethodCitations
SCV000577683GeneDxcriteria provided, single submitter
Likely pathogenic
(Jul 18, 2015)
germlineclinical testing

Citation Link,

SCV000856364EGL Genetic Diagnostics, Eurofins Clinical Diagnosticscriteria provided, single submitter
Uncertain significance
(Aug 29, 2017)
germlineclinical testing

Citation Link,

SCV001798671Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC) - VKGL Data-share Consensusno assertion criteria providedUncertain significancegermlineclinical testing

Summary from all submissions

EthnicityOriginAffectedIndividualsFamiliesChromosomes testedNumber TestedFamily historyMethod
not providedgermlineyesnot providednot providednot providednot providednot providedclinical testing
not providedgermlineunknown1not providednot providednot providednot providedclinical testing

Details of each submission

From GeneDx, SCV000577683.4

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testingnot provided

Description

The L146V variant in the AGA gene has not been published as a pathogenic variant, nor has it been reported as a benign polymorphism to our knowledge. The NHLBI ESP Exome Sequencing Project reports the L146V variant was observed in 13/8600 alleles (0.15%) and 23/4406 alleles (0.52%) from individuals of European and African background respectively, indicating it may be a rare variant in these populations; no individuals within these control groups were reported as homozygous for this variant. The L146V variant is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties. This substitution occurs at a position that is conserved across species, and in silico analysis predicts this variant is probably damaging to the protein structure/function. Missense variants in nearby residues (F135S and S147P) have been reported in the Human Gene Mutation Database in the homozygous state association with aspartylglucosaminuria (Stenson et al., 2014), supporting the functional importance of this region of the protein. The L146V variant is a strong candidate for a disease-causing variant, however the possibility it may be a rare benign variant cannot be excluded.

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

From EGL Genetic Diagnostics, Eurofins Clinical Diagnostics, SCV000856364.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not provided1not providednot providedclinical testingnot provided
#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineunknownnot providednot providednot provided1not providednot providednot provided

From Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC) - VKGL Data-share Consensus, SCV001798671.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testingnot provided
#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineyesnot providednot providednot providednot providednot providednot providednot provided

Last Updated: Sep 6, 2021

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