rs397516740

Variant names:

• chrX-120455461-C-T
• rs397516740
• NM_002294.3:c.293G>A

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1 PM2 PP5_Very_Strong

The NM_002294.3(LAMP2):​c.293G>A​(p.Trp98*) variant causes a stop gained change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★). Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 21)
• Consequence: LAMP2 NM_002294.3 stop_gained
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:4
• Conservation: PhyloP100: 5.24

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 18 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-120455461-C-T is Pathogenic according to our data. Variant chrX-120455461-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 44423.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-120455461-C-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
LAMP2	NM_002294.3	c.293G>A	p.Trp98*	stop_gained	Exon 3 of 9	ENST00000200639.9	NP_002285.1
LAMP2	NM_001122606.1	c.293G>A	p.Trp98*	stop_gained	Exon 3 of 9		NP_001116078.1
LAMP2	NM_013995.2	c.293G>A	p.Trp98*	stop_gained	Exon 3 of 9		NP_054701.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
LAMP2	ENST00000200639.9	c.293G>A	p.Trp98*	stop_gained	Exon 3 of 9	1	NM_002294.3	ENSP00000200639.4
LAMP2	ENST00000434600.6	c.293G>A	p.Trp98*	stop_gained	Exon 3 of 9	1		ENSP00000408411.2
LAMP2	ENST00000371335.4	c.293G>A	p.Trp98*	stop_gained	Exon 3 of 9	1		ENSP00000360386.4
LAMP2	ENST00000706600.1	c.293G>A	p.Trp98*	stop_gained	Exon 3 of 9			ENSP00000516464.1

Frequencies

GnomAD3 genomes Cov.: 21

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 21

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Danon disease Pathogenic:2

Jan 19, 2021

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

For these reasons, this variant has been classified as Pathogenic. This sequence change creates a premature translational stop signal (p.Trp98*) 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 (ExAC no frequency). This nonsense change has been observed in individual(s) with clinical features of Danon disease (PMID: 16565504). ClinVar contains an entry for this variant (Variation ID: 44423). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site, but this prediction has not been confirmed by published transcriptional studies. -

Mar 18, 2015

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Pathogenic:2

Jan 31, 2013

Stanford Center for Inherited Cardiovascular Disease, Stanford University

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: provider interpretation

- -

Apr 06, 2017

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

p.Trp98Ter (TGG>TAG): c.293 G>A in exon 3 of the LAMP2 gene (NM_002294.2). The Trp98Ter mutation in the LAMP2 gene has been reported previously in association with Danon disease (Fanin M et al., 2006; Boucek D et al., 2011; Miani D et al., 2012). Fanin et al. (2006) reported the Trp98Stop mutation in a male patient presenting with jaundice at age 12 who developed muscle weakness, Wolff-Parkinson-White (WPW) syndrome and hypertrophic cardiomyopathy by his 20s. His mother, who was heterozygous for Trp98Stop, had a history of WPW, mild muscle weakness and hypertrophic cardiomyopathy progressing to heart failure with subsequent heart transplant by age 52. Additionally, skeletal muscle from this male patient demonstrated near absence of LAMP2 protein, while his mother's LAMP2 protein levels were not significantly different from controls, highlighting the variability between males who harbor hemizygous mutations and female heterozygous carriers (Fanin M et al., 2006). Moreover, the Trp98Stop mutation is predicted to cause loss of normal protein function either through premature protein truncation or nonsense-mediated mRNA decay. Therefore, Trp98Stop in the LAMP2 gene is interpreted to be a disease-causing mutation. The variant is found in HCM panel(s). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.62	D
BayesDel_noAF	Pathogenic	0.60
CADD	Pathogenic	36
DANN	Uncertain	1.0
FATHMM_MKL	Uncertain	0.92	D
Vest4		0.82
GERP RS		5.4
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		2.8

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs397516740; hg19: chrX-119589316;