rs727503119

Positions:

• chrX-120446304-C-A
• chrX-120446304-C-T

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PVS1_Moderate PM2 PP5_Very_Strong

The ENST00000200639.9(LAMP2):​c.864+1G>T variant causes a splice donor change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Pathogenic (★★).

• Frequency: Genomes: not found (cov: 22)
• Consequence: LAMP2 ENST00000200639.9 splice_donor
• Scores: Splicing: ADA: 1.000
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:2
• Conservation: PhyloP100: 4.53

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: Splicing +-2 bp (donor or acceptor) variant, product NOT destroyed by NMD, known LOF gene, truncates exone, which is 0.09894566 fraction of the gene. No cryptic splice site detected. Exon removal is inframe change.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant X-120446304-C-A is Pathogenic according to our data. Variant chrX-120446304-C-A is described in ClinVar as [Pathogenic]. Clinvar id is 163813.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-120446304-C-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
LAMP2	NM_002294.3	c.864+1G>T		splice_donor_variant		ENST00000200639.9	NP_002285.1
LAMP2	NM_001122606.1	c.864+1G>T		splice_donor_variant			NP_001116078.1
LAMP2	NM_013995.2	c.864+1G>T		splice_donor_variant			NP_054701.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
LAMP2	ENST00000200639.9	c.864+1G>T		splice_donor_variant		1	NM_002294.3	ENSP00000200639	P3

Frequencies

GnomAD3 genomes Cov.: 22

GnomAD4 exome Cov.: 29

GnomAD4 genome Cov.: 22

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

Oct 08, 2013

The 864+1G>T variant in LAMP2 has now been identified by our laboratory as a de novo variant in a teenage female with HCM and LV dilation. This variant occurs i n the invariant region (+/- 1,2) of the splice consensus sequence and is predict ed to cause altered splicing leading to an abnormal or absent protein. Loss of f unction of the LAMP2 gene is associated with Danon disease, an X-linked glycogen storage disease that includes cardiomyopathy (HCM and DCM) and skeletal myopath y (Boucek 2011). In summary, this variant meets our criteria to be classified as pathogenic (http://pcpgm.partners.org/LMM) based upon predicted impact of the v ariant. -

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Aug 27, 2013

c.864+1 G>T: IVS6+1 G>T in intron 6 of the LAMP2 gene (NM_002294.2). Although the c.864+1 G>A mutation has not been reported as a disease-causing mutation or as a benign polymorphism to our knowledge, this mutation destroys the canonical splice donor site in intron 6 and is predicted to cause abnormal gene splicing. The mutation is predicted to lead to either an abnormal message that is subject to nonsense-mediated mRNA decay, or to an abnormal protein product if the message is used for protein translation. Other splice site mutations in the LAMP2 gene have been reported in association with Danon disease. In summary, c.864+1 G>A in the LAMP2 gene is interpreted as 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	0.33
CADD	Pathogenic	33
DANN	Uncertain	0.99
FATHMM_MKL	Pathogenic	0.98	D
MutationTaster	Benign	1.0	D;D;D;D;D
GERP RS		5.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		2.8

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.93
SpliceAI score (max)		0.99		Details are displayed if max score is > 0.2
DS_DL_spliceai		0.99		Position offset: 1

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

Publications

LitVar

Other links and lift over

dbSNP: rs727503119; hg19: chrX-119580159;