rs727504262

Positions:

• chrX-120441895-C-T

Variant summary

Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PVS1_Strong PM2 PP5

The ENST00000200639.9(LAMP2):​c.929-1G>A variant causes a splice acceptor change involving the alteration of a non-conserved nucleotide. 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 Likely pathogenic (no stars).

• Frequency: Genomes: not found (cov: 22)
• Consequence: LAMP2 ENST00000200639.9 splice_acceptor
• Scores: Splicing: ADA: 1.000
• Clinical Significance: Likely pathogenic no assertion criteria provided P:2
• Conservation: PhyloP100: 2.58

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 Likely_pathogenic. Variant got 7 ACMG points.

• PVS1: Splicing +-2 bp (donor or acceptor) variant, product NOT destroyed by NMD, known LOF gene, truncates exone, which is 0.13300893 fraction of the gene. Cryptic splice site detected, with MaxEntScore 7.5, offset of 7, new splice context is: cttttctttgaaattttcAGcat. Cryptic site results in frameshift change. If cryptic site found is not functional and variant results in exon loss, it results in inframe change.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant X-120441895-C-T is Pathogenic according to our data. Variant chrX-120441895-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 177657.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chrX-120441895-C-T is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
LAMP2	NM_002294.3	c.929-1G>A		splice_acceptor_variant		ENST00000200639.9	NP_002285.1
LAMP2	NM_001122606.1	c.929-1G>A		splice_acceptor_variant			NP_001116078.1
LAMP2	NM_013995.2	c.929-1G>A		splice_acceptor_variant			NP_054701.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
LAMP2	ENST00000200639.9	c.929-1G>A		splice_acceptor_variant		1	NM_002294.3	ENSP00000200639	P3

Frequencies

GnomAD3 genomes Cov.: 22

GnomAD4 exome Cov.: 28

GnomAD4 genome Cov.: 22

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:2

Revision: no assertion criteria provided

Submissions by phenotype

Danon disease Pathogenic:1

Likely pathogenic, no assertion criteria provided

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Feb 11, 2013

proposed classification - variant undergoing re-assessment, contact laboratory -

not provided Pathogenic:1

Likely pathogenic, no assertion criteria provided

provider interpretation

Stanford Center for Inherited Cardiovascular Disease, Stanford University

Oct 04, 2016

The patient provided a lab report for a relative with Danon disease. The test included sequencing of 10 genes associated with HCM: ACTC, LAMP2, MYBPC3, MYH7, MYL2, MYL3, PRKAG2, TNNI3, TNNT2, TPM1. A variant was found: hemizygous c.929-1G>A (formerly known as IVS7-1G>A) in intron 7 of the LAMP2 gene. c.929-1G>A (formerly known as IVS7-1G>A) in the LAMP2 gene (NM_002294.2) Given that this variant has been reported in another family with Danon disease, that the variant disturbs a canonical splice site and that it is absent from controls, we also consider this variant likely pathogenic and we do feel it is suitable for assessing risk in healthy relatives ("predictive genetic testing"). This variant was found in two siblings from Germany with Danon disease (Horvath et al 2003). The proband had Danon disease that was diagnosed at 25 years of age after heart failure due to hypertrophic cardiomyopathy. A pacemaker was placed. He developed generalized muscle weakness, eventually requiring a wheelchair. He later had a heart transplant. The proband's sister also experienced heart failure and had the variant. The variant was not present in 100 healthy controls. The nucleotide at position 929-1 is completely conserved across species. This variant disturbs a canonical splice site within the LAMP2 gene. Incorrect splicing predicts a loss of 55 amino acids from the LAMP-2 protein (Horvath et al 2003). Variants in the LAMP2 gene causing Danon disease are almost always truncating, frameshift or disturb splice sites. At least twenty-six patients with Danon disease are reported in the literature with variants in LAMP2 that disturb splice sites (Arad et al 2005, Boucek et al 2011, Horvath et al 2003 Maron et al 2009, Nishino et al 2000, Sugie et al 2002, Yang et al 2005). The variant was not present in the Exome Aggregation Consortium dataset (http://exac.broadinstitute.org/), which currently includes variant calls on ~64,000 individuals of European, African, Latino and Asian descent (as of October 2016). Coverage at this site is 60x. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.62	D
BayesDel_noAF	Uncertain	0.0
CADD	Pathogenic	34
DANN	Uncertain	0.99
FATHMM_MKL	Uncertain	0.88	D
MutationTaster	Benign	1.0	D;D;D;D;D
GERP RS		5.8

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.94
SpliceAI score (max)		0.99		Details are displayed if max score is > 0.2
DS_AG_spliceai		0.90		Position offset: -8
DS_AL_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: rs727504262; hg19: chrX-119575750;