NM_002294.3(LAMP2):c.1000G>C (p.Glu334Gln) AND Danon disease

Clinical significance:Conflicting interpretations of pathogenicity, Benign(1);Uncertain significance(1) (Last evaluated: Feb 18, 2020)

Review status:1 star out of maximum of 4 stars

criteria provided, conflicting interpretations

Based on:
2 submissions [Details]
Record status:
current
Accession:
RCV000801420.4

Allele description [Variation Report for NM_002294.3(LAMP2):c.1000G>C (p.Glu334Gln)]

NM_002294.3(LAMP2):c.1000G>C (p.Glu334Gln)

Gene:
LAMP2:lysosomal associated membrane protein 2 [Gene - OMIM - HGNC]
Variant type:
single nucleotide variant
Cytogenetic location:
Xq24
Genomic location:
Preferred name:
NM_002294.3(LAMP2):c.1000G>C (p.Glu334Gln)
HGVS:
  • NC_000023.11:g.120441823C>G
  • NG_007995.1:g.32527G>C
  • NM_001122606.1:c.1000G>C
  • NM_002294.2:c.1000G>C
  • NM_002294.3:c.1000G>CMANE SELECT
  • NM_013995.2:c.1000G>C
  • NP_001116078.1:p.Glu334Gln
  • NP_002285.1:p.Glu334Gln
  • NP_002285.1:p.Glu334Gln
  • NP_054701.1:p.Glu334Gln
  • LRG_749t1:c.1000G>C
  • LRG_749t2:c.1000G>C
  • LRG_749t3:c.1000G>C
  • LRG_749:g.32527G>C
  • LRG_749p1:p.Glu334Gln
  • LRG_749p2:p.Glu334Gln
  • LRG_749p3:p.Glu334Gln
  • NC_000023.10:g.119575678C>G
Protein change:
E334Q
Links:
dbSNP: rs766962315
NCBI 1000 Genomes Browser:
rs766962315
Molecular consequence:
  • NM_001122606.1:c.1000G>C - missense variant - [Sequence Ontology: SO:0001583]
  • NM_002294.2:c.1000G>C - missense variant - [Sequence Ontology: SO:0001583]
  • NM_002294.3:c.1000G>C - missense variant - [Sequence Ontology: SO:0001583]
  • NM_013995.2:c.1000G>C - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Name:
Danon disease
Synonyms:
PSEUDOGLYCOGENOSIS II; GSD IIb; LYSOSOMAL GLYCOGEN STORAGE DISEASE WITHOUT ACID MALTASE DEFICIENCY; See all synonyms [MedGen]
Identifiers:
MONDO: MONDO:0010281; MedGen: C0878677; Orphanet: 34587; OMIM: 300257

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Assertion and evidence details

Submission AccessionSubmitterReview Status
(Assertion method)
Clinical Significance
(Last evaluated)
OriginMethodCitations
SCV000941195Invitaecriteria provided, single submitter
Uncertain significance
(Feb 18, 2020)
germlineclinical testing

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

SCV001330065Illumina Clinical Services Laboratory,Illuminacriteria provided, single submitter
Benign
(Jan 13, 2018)
germlineclinical testing

Citation Link

Summary from all submissions

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

Citations

PubMed

Sherloc: a comprehensive refinement of the ACMG-AMP variant classification criteria.

Nykamp K, Anderson M, Powers M, Garcia J, Herrera B, Ho YY, Kobayashi Y, Patil N, Thusberg J, Westbrook M; Invitae Clinical Genomics Group., Topper S.

Genet Med. 2017 Oct;19(10):1105-1117. doi: 10.1038/gim.2017.37. Epub 2017 May 11. Erratum in: Genet Med. 2020 Jan;22(1):240-242.

PubMed [citation]
PMID:
28492532
PMCID:
PMC5632818

Details of each submission

From Invitae, SCV000941195.3

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

Description

This sequence change replaces glutamic acid with glutamine at codon 334 of the LAMP2 protein (p.Glu334Gln). The glutamic acid residue is highly conserved and there is a small physicochemical difference between glutamic acid and glutamine. This variant is present in population databases (rs766962315, ExAC 0.004%), including at least one homozygous and/or hemizygous individual. This variant has not been reported in the literature in individuals with LAMP2-related disease. ClinVar contains an entry for this variant (Variation ID: 449177). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: Tolerated; PolyPhen-2: Probably Damaging; Align-GVGD: Class C0). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.

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

From Illumina Clinical Services Laboratory,Illumina, SCV001330065.1

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

Description

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease.

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

Last Updated: Nov 27, 2021

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