X-120456650-C-T

Position:

• chrX-120456650-C-T

Variant summary

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

The NM_002294.3(LAMP2):​c.183+1G>A 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 Likely pathogenic (★★).

• Frequency:
  • Genomes: not found (cov: 22)
  • Exomes 𝑓: 0.0 (0 hom. 0 hem.)
  • Failed GnomAD Quality Control
• Consequence: LAMP2 NM_002294.3 splice_donor
• Scores: Splicing: ADA: 1.000
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:3
• Conservation: PhyloP100: 4.82

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 0.09570154 fraction of the gene. Cryptic splice site detected, with MaxEntScore 4.4, offset of -30, new splice context is: acaGTacgc. Cryptic site results in inframe change. If cryptic site found is not functional and variant results in exon loss, it results in frameshift change.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant X-120456650-C-T is Pathogenic according to our data. Variant chrX-120456650-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 163816.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-120456650-C-T is described in Lovd as [Pathogenic]. Variant chrX-120456650-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.183+1G>A		splice_donor_variant		ENST00000200639.9	NP_002285.1
LAMP2	NM_001122606.1	c.183+1G>A		splice_donor_variant			NP_001116078.1
LAMP2	NM_013995.2	c.183+1G>A		splice_donor_variant			NP_054701.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
LAMP2	ENST00000200639.9	c.183+1G>A		splice_donor_variant		1	NM_002294.3	ENSP00000200639	P3
LAMP2	ENST00000371335.4	c.183+1G>A		splice_donor_variant		1		ENSP00000360386	A1
LAMP2	ENST00000434600.6	c.183+1G>A		splice_donor_variant		1		ENSP00000408411	A1
LAMP2	ENST00000706600.1	c.183+1G>A		splice_donor_variant				ENSP00000516464

Frequencies

GnomAD3 genomes Cov.: 22

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 865456 Hom.: 0 Cov.: 13 AF XY: 0.00 AC XY: 0 AN XY: 241024

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 22

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Danon disease Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Apr 08, 2023

For these reasons, this variant has been classified as Pathogenic. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. ClinVar contains an entry for this variant (Variation ID: 163816). Disruption of this splice site has been observed in individuals with Danon disease and hypertrophic cardiomyopathy (PMID: 21415759, 27532257; Invitae). This variant is not present in population databases (gnomAD no frequency). This sequence change affects a donor splice site in intron 2 of the LAMP2 gene. It is expected to disrupt RNA splicing. Variants that disrupt the donor or acceptor splice site typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in LAMP2 are known to be pathogenic (PMID: 21415759). -

Hypertrophic cardiomyopathy Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Sep 30, 2020

The c.183+1G>A variant in LAMP2 has been reported in at least 4 individuals with clinical features of Danon disease, including a reportedly de novo occurrence (Boucek 2011 PMID: 21415759, Alfares 2015 PMID: 25611685; Walsh 2017 PMID: 27532257; LMM internal data; Invitae pers. comm.). This variant has also been reported by other clinical laboratories in ClinVar (Variation ID 163816) and was absent from large population studies. This variant occurs within the canonical splice site (+/- 1,2) and is predicted to cause altered splicing leading to an abnormal or absent protein. Loss of function of the LAMP2 gene is an established disease mechanism in X-linked Danon disease. In summary, this variant meets criteria to be classified as pathogenic for X-linked Danon disease. ACMG/AMP Criteria applied: PVS1_Strong, PM2, PM6, PS4_Moderate. -

Cardiovascular phenotype Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Jun 27, 2023

The c.183+1G>A intronic variant results from a G to A substitution one nucleotide after coding exon 2 of the LAMP2 gene. In silico splice site analysis predicts that this alteration will weaken the native splice donor site. The stop codon in the predicted resulting transcript occurs in the 5' end ofthe LAMP2 gene. As such, this alteration may escape nonsense-mediated mRNAdecay and/or be prone to rescue by reinitiation (Rivas et al. Science. 2015 May 8;348(6235):666-9; Lindeboom et al. Nat Genet. 2016 Oct;48(10):1112-8; Rhee et al. Sci Rep. 2017 May 10;7(1):1653). The exact functional effect of this alteration is unknown; however, the impacted region is critical for protein function (Ambry internal data). This variant has been previously reported in a cohort of patients reported to have Danon disease, and in a hypertrophic cardiomyopathy cohort (Boucek D et al. Genet Med, 2011 Jun;13:563-8; Walsh R et al. Genet Med, 2017 Feb;19:192-203). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). This nucleotide position is highly conserved in available vertebrate species. Based on the majority of available evidence to date, this variant is likely to be pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.62	D
BayesDel_noAF	Uncertain	-0.040
CADD	Pathogenic	26
DANN	Uncertain	0.98
FATHMM_MKL	Uncertain	0.91	D
MutationTaster	Benign	1.0	D;D;D;D;D
GERP RS		4.5

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.75
SpliceAI score (max)		1.0		Details are displayed if max score is > 0.2
DS_DL_spliceai		1.0		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: rs727503120; hg19: chrX-119590505;