rs727503118

Positions:

• chrX-120442650-G-A
• chrX-120442650-G-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.877C>T​(p.Arg293*) 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: 22)
• Consequence: LAMP2 NM_002294.3 stop_gained
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:5
• Conservation: PhyloP100: 3.87

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-120442650-G-A is Pathogenic according to our data. Variant chrX-120442650-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 163812.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-120442650-G-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
LAMP2	NM_002294.3	c.877C>T	p.Arg293*	stop_gained	7/9	ENST00000200639.9	NP_002285.1
LAMP2	NM_001122606.1	c.877C>T	p.Arg293*	stop_gained	7/9		NP_001116078.1
LAMP2	NM_013995.2	c.877C>T	p.Arg293*	stop_gained	7/9		NP_054701.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
LAMP2	ENST00000200639.9	c.877C>T	p.Arg293*	stop_gained	7/9	1	NM_002294.3	ENSP00000200639.4

Frequencies

GnomAD3 genomes Cov.: 22

GnomAD4 exome Cov.: 29

GnomAD4 genome Cov.: 22

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	Clinical Genetics Laboratory, Skane University Hospital Lund	May 27, 2022	- -
Pathogenic, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	May 02, 2017	- -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Mar 30, 2023	Not observed at significant frequency in large population cohorts (gnomAD); Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss of function is a known mechanism of disease; This variant is associated with the following publications: (PMID: 27532257, 22695892, 18465145, 20445193, 28138913, 21896538) -

Danon disease Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Sep 24, 2022

Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 163812). This premature translational stop signal has been observed in individuals with Danon disease or hypertrophic cardiomyopathy (PMID: 20960602, 21896538, 23168931). This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Arg293*) 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). -

Hypertrophic cardiomyopathy;C0878677:Danon disease Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Apr 23, 2015

The p.Arg293X variant in LAMP2 has been reported in 4 individuals with with clin ical findings consistent with Danon disease and occured de novo in 1 of these in dividuals (Lascone 2008, Katznerg 201, Garcia-Pavia 2011). The variant was abse nt from large population studies. This nonsense variant leads to a premature ter mination codon at position 293, which is predicted to lead to a truncated or abs ent protein. Loss of function of the LAMP2 gene is known to cause Danon disease, an X-lined glycogen storage disease that includes cardiomyopathy (HCM and DCM) and skeletal myopathy (Boucek 2011). In summary, this variant meets our criteria to be classified as pathogenic for Danon disease in an X-linked dominant manner (http://www.partners.org/personalizedmedicine/LMM) based upon predicted impact to the protein, de novo occurrence, and absence from controls. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.62	D
BayesDel_noAF	Pathogenic	0.58
CADD	Pathogenic	40
DANN	Uncertain	1.0
FATHMM_MKL	Uncertain	0.84	D
Vest4		0.84
GERP RS		5.3
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.21		Details are displayed if max score is > 0.2
DS_AL_spliceai		0.21		Position offset: 12

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

Publications

LitVar

Other links and lift over

dbSNP: rs727503118; hg19: chrX-119576505; COSMIC: COSV52355176;