Submissions for variant NM_002294.3(LAMP2):c.659dup (p.Gly221fs)

dbSNP: rs1556101640

Total submissions: 2

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000482621	SCV000569770	likely pathogenic	not provided	2016-03-29	criteria provided, single submitter	clinical testing	Although the c.659dupC likely pathogenic variant in the LAMP2 gene has not been reported to our knowledge, this variant causes a shift in reading frame starting at codon Glycine 221, changing it to a Tryptophan, and creating a premature stop codon at position 6 of the new reading frame, denoted p.Gly221TrpfsX6. This variant is expected to result in either an abnormal, truncated protein product or loss of protein from this allele through nonsense-mediated mRNA decay. In addition, other frameshift variants in the LAMP2 gene have been reported in HGMD in association with Danon disease (Stenson et al., 2014). Furthermore, the c.659dupC variant 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, c.659dupC in the LAMP2 gene is interpreted as a likely pathogenic variant.
Labcorp Genetics (formerly Invitae), Labcorp	RCV001382578	SCV001581418	pathogenic	Danon disease	2020-06-24	criteria provided, single submitter	clinical testing	For these reasons, this variant has been classified as Pathogenic. Loss-of-function variants in LAMP2 are known to be pathogenic (PMID: 21415759). This variant has not been reported in the literature in individuals with LAMP2-related conditions. ClinVar contains an entry for this variant (Variation ID: 420796). This variant is not present in population databases (ExAC no frequency). This sequence change creates a premature translational stop signal (p.Gly221Trpfs*6) in the LAMP2 gene. It is expected to result in an absent or disrupted protein product.