rs727504597

Variant names:

• chrX-120441802-CA-C
• rs727504597
• NM_002294.3:c.1020delT

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.1020delT​(p.Gly341GlufsTer5) 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: 0.922

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 0.173 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-120441802-CA-C is Pathogenic according to our data. Variant chrX-120441802-CA-C is described in ClinVar as [Pathogenic]. Clinvar id is 178999.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.1020delT	p.Gly341GlufsTer5	frameshift_variant	Exon 8 of 9	ENST00000200639.9	NP_002285.1
LAMP2	NM_001122606.1	c.1020delT	p.Gly341GlufsTer5	frameshift_variant	Exon 8 of 9		NP_001116078.1
LAMP2	NM_013995.2	c.1020delT	p.Gly341GlufsTer5	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.1020delT	p.Gly341GlufsTer5	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

Primary dilated cardiomyopathy;C0878677:Danon disease Pathogenic:1

Jun 12, 2013

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The Gly341fs variant in LAMP2 has not been reported in individuals with cardiomy opathy and data from large population studies is insufficient to assess its freq uency. This frameshift variant is predicted to alter the protein?s amino acid se quence beginning at position 341 and lead to a premature termination codon 5 ami no acids downstream. This alteration is then predicted to lead to a truncated or absent protein. Loss of function of the LAMP2 gene is an established disease me chanism in Danon disease. In summary, this variant meets our criteria to be clas sified as pathogenic (http://pcpgm.partners.org/LMM) based upon its predicted im pact and established pathogenicity of this type of variant. -

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: rs727504597; hg19: chrX-119575657;