ClinVar Miner

Submissions for variant NM_002294.3(LAMP2):c.928G>A (p.Val310Ile) (rs104894858)

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Total submissions: 8
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Laboratory for Molecular Medicine, Partners HealthCare Personalized Medicine RCV000844638 SCV000061093 pathogenic Danon disease; Hypertrophic cardiomyopathy 2014-02-20 criteria provided, single submitter clinical testing The p.Val310Ile variant in LAMP2 has been reported in multiple individuals with HCM or Danon disease, where it showed segregation with disease in multiple famil ies and de novo occurrence in at least 1 family (Arad 2005, Bertini 2005, Burusn ukul, 2008, Maron 2009, Sabourdy 2009, LMM data). It has not been identified in large population studies. It was shown to alter splicing of the LAMP2 mRNA, resu lting in a frameshift and subsequent premature termination in exon 8 (Arad 2005, Sabourdy 2009). This variant has been identified in ClinVar (Variant ID: 9982). Loss of function of the LAMP2 gene is an established disease mechanism and is t ypically associated with Danon disease. In summary, this variant meets criteria to be classified as pathogenic.
GeneDx RCV000157981 SCV000207916 pathogenic not provided 2020-09-10 criteria provided, single submitter clinical testing Destroys a canonical splice donor site and results in the skipping of exon 7 (Arad et al., 2005); Not observed in large population cohorts (Lek et al., 2016); This variant is associated with the following publications: (PMID: 18555174, 25611685, 29753918, 16217705, 15673802, 22695892, 19373884, 19318653, 20173215, 12398843, 27600940, 27532257, 33763395)
Invitae RCV000010663 SCV001401143 pathogenic Danon disease 2020-10-20 criteria provided, single submitter clinical testing This sequence change replaces valine with isoleucine at codon 310 of the LAMP2 protein (p.Val310Ile). The valine residue is weakly conserved and there is a small physicochemical difference between valine and isoleucine. RNA analysis indicates that this variant induces altered splicing and may result in an absent or disrupted protein product. This variant is not present in population databases (ExAC no frequency). This variant has been observed in individual(s) with Danon disease or dilated cardiomyopathy (PMID: 16217705, 15673802, 29753918, 19373884, 29753918). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 9982). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. Nucleotide substitutions within the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Studies have shown that this variant is associated with skipping of exon 7, which introduces a frameshift (PMID: 16217705, 19373884). The resulting mRNA is expected to undergo nonsense-mediated decay. For these reasons, this variant has been classified as Pathogenic.
OMIM RCV000010663 SCV000030889 pathogenic Danon disease 2005-01-27 no assertion criteria provided literature only
Institute of Human Genetics, Klinikum rechts der Isar RCV000010663 SCV001149822 pathogenic Danon disease 2018-12-11 no assertion criteria provided clinical testing
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen RCV000157981 SCV001742174 pathogenic not provided no assertion criteria provided clinical testing
Genome Diagnostics Laboratory, University Medical Center Utrecht RCV000157981 SCV001932866 pathogenic not provided no assertion criteria provided clinical testing
Human Genetics - Radboudumc,Radboudumc RCV000157981 SCV001952843 pathogenic not provided no assertion criteria provided clinical testing

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