rs104894857

Positions:

• chrX-120449006-G-A
• chrX-120449006-G-T

Variant summary

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

The NM_002294.3(LAMP2):​c.520C>T​(p.Gln174Ter) 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: 23)
• Consequence: LAMP2 NM_002294.3 stop_gained
• Clinical Significance: Pathogenic criteria provided, single submitter P:2
• Conservation: PhyloP100: 4.10

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-120449006-G-A is Pathogenic according to our data. Variant chrX-120449006-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 9981.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chrX-120449006-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.520C>T	p.Gln174Ter	stop_gained	4/9	ENST00000200639.9	NP_002285.1
LAMP2	NM_001122606.1	c.520C>T	p.Gln174Ter	stop_gained	4/9		NP_001116078.1
LAMP2	NM_013995.2	c.520C>T	p.Gln174Ter	stop_gained	4/9		NP_054701.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
LAMP2	ENST00000200639.9	c.520C>T	p.Gln174Ter	stop_gained	4/9	1	NM_002294.3	ENSP00000200639	P3

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD4 exome Cov.: 29

GnomAD4 genome Cov.: 23

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, single submitter

Submissions by phenotype

Danon disease Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 04, 2023	For these reasons, this variant has been classified as Pathogenic. Experimental studies have shown that this premature translational stop signal affects LAMP2 function (PMID: 27678261). Algorithms developed to predict the effect of variants on protein structure and function are not available or were not evaluated for this variant. ClinVar contains an entry for this variant (Variation ID: 9981). This premature translational stop signal has been observed in individual(s) with Danon disease (PMID: 15253947, 27678261). It has also been observed to segregate with disease in related individuals. This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Gln174*) 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). -
Pathogenic, no assertion criteria provided	literature only	OMIM	Aug 01, 2004	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.62	D
BayesDel_noAF	Pathogenic	0.63
CADD	Pathogenic	36
DANN	Uncertain	1.0
FATHMM_MKL	Pathogenic	0.97	D
MutationTaster	Benign	1.0	A;A;A;A;A
Vest4		0.89
GERP RS		5.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7

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: rs104894857; hg19: chrX-119582861;