rs876657696

Positions:

• chrX-120455460-C-T

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.294G>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: 20)
• Consequence: LAMP2 NM_002294.3 stop_gained
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:2
• 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-120455460-C-T is Pathogenic according to our data. Variant chrX-120455460-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 228356.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-120455460-C-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
LAMP2	NM_002294.3	c.294G>A	p.Trp98*	stop_gained	3/9	ENST00000200639.9	NP_002285.1
LAMP2	NM_001122606.1	c.294G>A	p.Trp98*	stop_gained	3/9		NP_001116078.1
LAMP2	NM_013995.2	c.294G>A	p.Trp98*	stop_gained	3/9		NP_054701.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
LAMP2	ENST00000200639.9	c.294G>A	p.Trp98*	stop_gained	3/9	1	NM_002294.3	ENSP00000200639.4
LAMP2	ENST00000434600.6	c.294G>A	p.Trp98*	stop_gained	3/9	1		ENSP00000408411.2
LAMP2	ENST00000371335.4	c.294G>A	p.Trp98*	stop_gained	3/9	1		ENSP00000360386.4
LAMP2	ENST00000706600.1	c.294G>A	p.Trp98*	stop_gained	3/9			ENSP00000516464.1

Frequencies

GnomAD3 genomes Cov.: 20

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 20

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Danon disease Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Mar 18, 2015

The p.Trp98X variant in LAMP2 was absent from large population studies but has b een reported in 2 individuals with Danon disease and segregated with disease in 5 affected relatives from 1 family (Fanin 2006, Spinazzi 2008, Miani 2012). A di fferent DNA change resulting in the same protein change (c.293G>A, p.Trp98X) has also been identified by our laboratory in 1 individual with Danon disease. This nonsense variant leads to a premature termination codon at position 98 and has been shown to reduced LAMP2 mRNA levels, resulting in absent LAMP2 protein in a male patient (Fanin 2006). Loss of function of the LAMP2 gene is an established disease mechanism in individuals with Danon disease. In summary, this variant me ets our criteria to be classified as pathogenic for Danon disease in X-linked do minant manner (http://www.partners.org/personalizedmedicine/LMM) based upon its functional impact and segregation in affected individuals. -

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Blueprint Genetics

Jan 17, 2018

- -

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	0.91	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)		0.010		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: rs876657696; hg19: chrX-119589315;