ClinVar Miner

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

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Total submissions: 5
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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 2017-05-31 criteria provided, single submitter clinical testing p.Val310Ile (GTT>ATT): c.928 G>A in exon 7 of the LAMP2 gene (NM_002294.2). The V310I mutation in the LAMP2 gene has been reported in association with Danon disease and HCM (Arad et al., 2005; Bertini et al., 2005; Maron et. al., 2009). Arad et. al. (2005) identified the V310I mutation in two unrelated males. One male presented with classical Danon disease. His mother was affected with HCM and harbored the mutation. A mosaic V310I mutation was identified in the second male with HCM. Similarly, Bertini et al. (2005) identified V310I in two unrelated males with HCM. One individual with a de novo V310I mutation was identified in infancy with hypotonia and HCM. The other individual had a maternally inherited V310I mutation and presented in childhood with classical Danon disease. His mother was diagnosed at age 33 with HCM. The V310I mutation destroys a canonical splice donor site and results in the skipping of exon 7 (Arad et al., 2005). Other splice site mutations in the LAMP2 gene have been reported in association with Danon disease. Furthermore, the V310I mutation was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. In summary, V310I in the LAMP2 gene is interpreted as a disease-causing mutation. The variant is found in CARDIOMYOPATHY panel(s).
Institute of Human Genetics,Klinikum rechts der Isar RCV000010663 SCV001149822 pathogenic Danon disease 2018-12-11 criteria provided, single submitter clinical testing
Invitae RCV000010663 SCV001401143 pathogenic Danon disease 2019-07-24 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. This variant also falls at the last nucleotide of exon 7 of the LAMP2 coding sequence, which is part of the consensus splice site for this exon. This variant is not present in population databases (ExAC no frequency). This variant has been observed in several males with Danon disease, including a de novo occurrence (PMID: 16217705, 15673802, 29753918, 19373884). This variant has also been observed in females with dilated cardiomyopathy (PMID: 29753918). 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). Experimental studies have shown that this variant disrupts mRNA splicing (PMID: 16217705, 19373884). 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

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