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

dbSNP: rs104894858

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory for Molecular Medicine, Mass General Brigham 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)
Institute of Human Genetics Munich, Klinikum Rechts Der Isar, TU München	RCV000010663	SCV001149822	pathogenic	Danon disease	2018-12-11	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV000010663	SCV001401143	pathogenic	Danon disease	2023-08-20	criteria provided, single submitter	clinical testing	ClinVar contains an entry for this variant (Variation ID: 9982). This sequence change replaces valine, which is neutral and non-polar, with isoleucine, which is neutral and non-polar, at codon 310 of the LAMP2 protein (p.Val310Ile). RNA analysis indicates that this missense change induces altered splicing and may result in an absent or disrupted protein product. This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with Danon disease or dilated cardiomyopathy (PMID: 15673802, 16217705, 19373884, 29753918). In at least one individual the variant was observed to be de novo. An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be tolerated. Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Studies have shown that this missense change results in skipping of exon 7 and introduces a premature termination codon (PMID: 16217705, 19373884). The resulting mRNA is expected to undergo nonsense-mediated decay. For these reasons, this variant has been classified as Pathogenic.
Ambry Genetics	RCV002371769	SCV002686542	pathogenic	Cardiovascular phenotype	2021-03-19	criteria provided, single submitter	clinical testing	The c.928G>A pathogenic mutation (also known as p.V310I), located in coding exon 7 of the LAMP2 gene, results from a G to A substitution at nucleotide position 928. The amino acid change results in valine to isoleucine at codon 310, an amino acid with highly similar properties. However, this change occurs in the last base pair of coding exon 7, which makes it likely to have some effect on normal mRNA splicing. This alteration has been reported de novo in a subject with hypertrophic cardiomyopathy (HCM) and Danon disease (Arad M et al. N Engl J Med, 2005 Jan;352:362-72). In addition, this mutation has been reported in HCM cohorts, subjects with Danon disease as well as other subjects with features of LAMP2-related disease (Sabourdy F et al. Muscle Nerve, 2009 Jun;39:837-44; Alfares AA et al. Genet Med, 2015 Nov;17:880-8; Walsh R et al. Genet Med, 2017 02;19:192-203; Gourzi P et al. Eur J Med Genet, 2019 Jan;62:77-80). This nucleotide position is highly conserved in available vertebrate species. In silico splice site analysis predicts that this alteration will weaken the native splice donor site. In addition, as a missense substitution this is predicted to be tolerated by in silico analysis. Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation.
OMIM	RCV000010663	SCV000030889	pathogenic	Danon disease	2005-01-27	no assertion criteria provided	literature only
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
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV000157981	SCV001952843	pathogenic	not provided		no assertion criteria provided	clinical testing