X-120441729-C-T

Variant names:

• chrX-120441729-C-T
• rs727504742
• NM_002294.3:c.1093+1G>A

Variant summary

Our verdict is Pathogenic. The variant received 14 ACMG points: 14P and 0B. PVS1_Strong PM2 PP5_Very_Strong

The NM_002294.3(LAMP2):​c.1093+1G>A variant causes a splice donor, intron change involving the alteration of a 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 Pathogenic (★★).

• Frequency: Genomes: not found (cov: 23)
• Consequence: LAMP2 NM_002294.3 splice_donor, intron
• Scores: Splicing: ADA: 1.000
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:3
• Conservation: PhyloP100: 7.39
• Publications: 2 publications found

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]

LAMP2 Gene-Disease associations (from GenCC):

• Danon disease

  Inheritance: XL Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: ClinGen, G2P, Labcorp Genetics (formerly Invitae), Genomics England PanelApp, Orphanet

ACMG classification

Our verdict: Pathogenic. The variant received 14 ACMG points.

• PVS1: Splicing +-2 bp (donor or acceptor) variant, product NOT destroyed by NMD, known LOF gene, truncates exone, which is 0.13381995 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-120441729-C-T is Pathogenic according to our data. Variant chrX-120441729-C-T is described in ClinVar as Pathogenic. ClinVar VariationId is 179254.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
LAMP2	NM_002294.3	c.1093+1G>A		splice_donor_variant, intron_variant	Intron 8 of 8	ENST00000200639.9	NP_002285.1
LAMP2	NM_001122606.1	c.1093+1G>A		splice_donor_variant, intron_variant	Intron 8 of 8		NP_001116078.1
LAMP2	NM_013995.2	c.1093+1G>A		splice_donor_variant, intron_variant	Intron 8 of 8		NP_054701.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
LAMP2	ENST00000200639.9	c.1093+1G>A		splice_donor_variant, intron_variant	Intron 8 of 8	1	NM_002294.3	ENSP00000200639.4

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD4 exome Cov.: 27

GnomAD4 genome Cov.: 23

Alfa AF: 0.00 Hom.: 0

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Danon disease Pathogenic:2

Apr 12, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change affects a donor splice site in intron 8 of the LAMP2 gene. While this variant is not anticipated to result in nonsense mediated decay, it likely alters RNA splicing and results in a disrupted protein product. This variant is not present in population databases (gnomAD no frequency). Disruption of this splice site has been observed in individual(s) with Danon disease and/or LAMP2-related conditions (PMID: 18061453, 18990578). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 179254). Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Studies have shown that disruption of this splice site is associated with altered splicing resulting in multiple RNA products (PMID: 18061453, 18990578). For these reasons, this variant has been classified as Pathogenic.

Aug 29, 2013

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The 1093+1G>A variant in LAMP2 has not been previously reported in individuals w ith cardiomyopathy or Danon disease, or been observed in large population studie s. This variant occurs in the invariant region (+/- 1,2) of the splice consensus sequence and is predicted to cause altered splicing leading to an abnormal or a bsent protein (loss of function). Two other variants at this splice site (1093+1 G>C and 1093+2T>A) have been reported in individuals with Danon disease and were shown to alter splicing (DiBlasi 2008, Tu?on 2008). Loss of function variants i n LAMP2 are associated with Danon disease, an X-linked 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 (http ://pcpgm.partners.org/LMM) based on the predicted impact of the variant.

not provided Pathogenic:1

May 10, 2016

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Although the c.1093+1 G>A variant has not been published as a pathogenic variant or as a benign variant to our knowledge, it is classified in ClinVar as a pathogenic variant in association with Danon disease (ClinVar SCV000205754.2; Landrum et al., 2016). Furthermore, it destroys the canonical splice donor site in intron 8 and is predicted to cause abnormal gene splicing. This variant 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 variants in the LAMP2 gene, including two other variants at the same splice site, have been reported in HGMD in association with Danon disease (Stenson et al., 2014). Furthermore, the c.1093+1 G>A variant was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.62	D
BayesDel_noAF	Pathogenic	0.42
CADD	Pathogenic	32
DANN	Uncertain	1.0
DEOGEN2	Benign	0.0	.;.;.
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Benign	0.0	.;.;.
MetaRNN	Benign	0.0	.;.;.
MutationAssessor	Benign	0.0	.;.;.
PhyloP100		7.4
PROVEAN	Benign	0.0	.;.;.
REVEL	Benign	0.0
Sift	Pathogenic	0.0	.;.;.
Sift4G	Pathogenic	0.0	.;.;.
Vest4		0.0
GERP RS		5.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		2.8
Mutation Taster		=0/100	disease causing (ClinVar)

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_DL_spliceai		0.99		Position offset: 1

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

Other links and lift over

dbSNP: rs727504742; hg19: chrX-119575584;