ClinVar Miner

Submissions for variant NM_013995.2(LAMP2):c.1000G>C (p.Glu334Gln) (rs766962315)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000522587 SCV000617012 uncertain significance not provided 2016-08-12 criteria provided, single submitter clinical testing A variant of uncertain significance has been identified in the LAMP2 gene. The E334Q variant has not been published as a pathogenic variant, nor has it been reported as a benign variant to our knowledge. This variant was not observed in approximately 6,500 individuals of European and African American ancestry in an external variant database, indicating it is not a common benign variant in these populations. The E334Q variant is a semi-conservative amino acid substitution, which may impact secondary protein structure as these residues differ in some properties. In addition, 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. However, no missense variants in nearby residues have been reported in the Human Gene Mutation Database (Stenson et al., 2014). Furthermore, although this variant was previously identified in one other unrelated individual referred for cardiomyopathy genetic testing at GeneDx, family studies were not performed to discern whether this variant co-segregates with disease.Therefore, based on the currently available information, it is unclear whether this variant is pathogenic or benign.
Invitae RCV000801420 SCV000941195 uncertain significance Danon disease 2019-11-05 criteria provided, single submitter clinical testing 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.
Illumina Clinical Services Laboratory,Illumina RCV000801420 SCV001330065 benign Danon disease 2018-01-13 criteria provided, single submitter clinical testing 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.

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