rs1556092459

Variant names:

• chrX-120441849-A-AG
• rs1556092459
• NM_002294.3:c.973dupC

Variant summary

Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PVS1_Strong PM2 PP5_Moderate

The NM_002294.3(LAMP2):​c.973dupC​(p.Leu325ProfsTer25) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic (★).

• Frequency: Genomes: not found (cov: 23)
• Consequence: LAMP2 NM_002294.3 frameshift
• Clinical Significance: Pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 0.224

Genes affected

LAMP2 (HGNC:6501): (lysosomal associated membrane protein 2) The protein encoded by this gene is a member of a family of membrane glycoproteins. This glycoprotein provides selectins with carbohydrate ligands. It may play a role in tumor cell metastasis. It may also function in the protection, maintenance, and adhesion of the lysosome. Alternative splicing of this gene results in multiple transcript variants encoding distinct proteins. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Likely_pathogenic. Variant got 8 ACMG points.

• PVS1: Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most 50 bp of the penultimate exon, not predicted to undergo nonsense mediated mRNA decay. Fraction of 0.211 CDS is truncated, and there are 0 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant X-120441849-A-AG is Pathogenic according to our data. Variant chrX-120441849-A-AG is described in ClinVar as [Pathogenic]. Clinvar id is 409224.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
LAMP2	NM_002294.3	c.973dupC	p.Leu325ProfsTer25	frameshift_variant	Exon 8 of 9	ENST00000200639.9	NP_002285.1
LAMP2	NM_001122606.1	c.973dupC	p.Leu325ProfsTer25	frameshift_variant	Exon 8 of 9		NP_001116078.1
LAMP2	NM_013995.2	c.973dupC	p.Leu325ProfsTer25	frameshift_variant	Exon 8 of 9		NP_054701.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
LAMP2	ENST00000200639.9	c.973dupC	p.Leu325ProfsTer25	frameshift_variant	Exon 8 of 9	1	NM_002294.3	ENSP00000200639.4

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD4 exome Cov.: 28

GnomAD4 genome Cov.: 23

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

Danon disease Pathogenic:1

Feb 22, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change creates a premature translational stop signal (p.Leu325Profs*25) in the LAMP2 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in LAMP2 are known to be pathogenic (PMID: 21415759). This variant is not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individual(s) with Danon disease (PMID: 27179547). This variant is also known as c.973insC. ClinVar contains an entry for this variant (Variation ID: 409224). For these reasons, this variant has been classified as Pathogenic. -

Computational scores

Source: dbNSFP v4.3

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs1556092459; hg19: chrX-119575704;