rs727504648

Variant names:

• chrX-120446316-CAA-C
• rs727504648
• NM_002294.3:c.851_852delTT

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PVS1 PM2 PP5_Moderate

The NM_002294.3(LAMP2):​c.851_852delTT​(p.Phe284CysfsTer7) variant causes a frameshift change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic (★). Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 22)
• Consequence: LAMP2 NM_002294.3 frameshift
• Clinical Significance: Pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 5.30

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 Pathogenic. Variant got 12 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant X-120446316-CAA-C is Pathogenic according to our data. Variant chrX-120446316-CAA-C is described in ClinVar as [Pathogenic]. Clinvar id is 179126.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.851_852delTT	p.Phe284CysfsTer7	frameshift_variant	Exon 6 of 9	ENST00000200639.9	NP_002285.1
LAMP2	NM_001122606.1	c.851_852delTT	p.Phe284CysfsTer7	frameshift_variant	Exon 6 of 9		NP_001116078.1
LAMP2	NM_013995.2	c.851_852delTT	p.Phe284CysfsTer7	frameshift_variant	Exon 6 of 9		NP_054701.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
LAMP2	ENST00000200639.9	c.851_852delTT	p.Phe284CysfsTer7	frameshift_variant	Exon 6 of 9	1	NM_002294.3	ENSP00000200639.4

Frequencies

GnomAD3 genomes Cov.: 22

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome Cov.: 22

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

Danon disease Pathogenic:1

Nov 08, 2013

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The Phe284fs variant in LAMP2 has not been reported in individuals with cardiomy opathy or Danon disease. Data from large population studies is insufficient to a ssess whether this variant is present in the general population. This frameshift variant is predicted to alter the protein?s amino acid sequence beginning at po sition 284 and lead to a premature termination codon 7 amino acids downstream. T his alteration is then predicted to lead to a truncated or absent protein (loss of function; LOF). Heterozygous loss of function of the LAMP2 gene is an establi shed disease mechanism in Danon disease. In summary, this variant meets our crit eria to be classified as pathogenic (http://pcpgm.partners.org/LMM) based on the predicted impact of the variant. -

Computational scores

Source: dbNSFP v4.3

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs727504648; hg19: chrX-119580171;