X-120442599-C-T

Position:

• chrX-120442599-C-T

Variant summary

Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PM2 PM5 PP3_Strong PP5_Very_Strong

The NM_002294.3(LAMP2):​c.928G>A​(p.Val310Ile) variant causes a missense, splice region 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 (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V310F) has been classified as Pathogenic.

• Frequency: Genomes: not found (cov: 22)
• Consequence: LAMP2 NM_002294.3 missense, splice_region
• Scores: Splicing: ADA: 0.9999
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:9
• Conservation: PhyloP100: 4.51

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 16 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chrX-120442599-C-A is described in ClinVar as [Pathogenic]. Clinvar id is 835011.Status of the report is criteria_provided_single_submitter, 1 stars.
• PP3: Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF, max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.
• PP5: Variant X-120442599-C-T is Pathogenic according to our data. Variant chrX-120442599-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 9982.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-120442599-C-T is described in Lovd as [Pathogenic]. Variant chrX-120442599-C-T is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
LAMP2	NM_002294.3	c.928G>A	p.Val310Ile	missense_variant, splice_region_variant	7/9	ENST00000200639.9
LAMP2	NM_001122606.1	c.928G>A	p.Val310Ile	missense_variant, splice_region_variant	7/9
LAMP2	NM_013995.2	c.928G>A	p.Val310Ile	missense_variant, splice_region_variant	7/9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
LAMP2	ENST00000200639.9	c.928G>A	p.Val310Ile	missense_variant, splice_region_variant	7/9	1	NM_002294.3	P3

Frequencies

GnomAD3 genomes Cov.: 22

GnomAD4 exome Cov.: 28

GnomAD4 genome Cov.: 22

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:9

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:4

Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Sep 10, 2020	Destroys a canonical splice donor site and results in the skipping of exon 7 (Arad et al., 2005); Not observed in large population cohorts (Lek et al., 2016); This variant is associated with the following publications: (PMID: 18555174, 25611685, 29753918, 16217705, 15673802, 22695892, 19373884, 19318653, 20173215, 12398843, 27600940, 27532257, 33763395) -
Pathogenic, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Pathogenic, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Pathogenic, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -

Danon disease Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	Institute of Human Genetics Munich, Klinikum Rechts Der Isar, TU München	Dec 11, 2018	- -
Pathogenic, no assertion criteria provided	literature only	OMIM	Jan 27, 2005	- -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Aug 20, 2023	ClinVar contains an entry for this variant (Variation ID: 9982). This sequence change replaces valine, which is neutral and non-polar, with isoleucine, which is neutral and non-polar, at codon 310 of the LAMP2 protein (p.Val310Ile). RNA analysis indicates that this missense change induces altered splicing and may result in an absent or disrupted protein product. This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with Danon disease or dilated cardiomyopathy (PMID: 15673802, 16217705, 19373884, 29753918). In at least one individual the variant was observed to be de novo. An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be tolerated. Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Studies have shown that this missense change results in skipping of exon 7 and introduces a premature termination codon (PMID: 16217705, 19373884). The resulting mRNA is expected to undergo nonsense-mediated decay. For these reasons, this variant has been classified as Pathogenic. -

Hypertrophic cardiomyopathy;C0878677:Danon disease Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Feb 20, 2014

The p.Val310Ile variant in LAMP2 has been reported in multiple individuals with HCM or Danon disease, where it showed segregation with disease in multiple famil ies and de novo occurrence in at least 1 family (Arad 2005, Bertini 2005, Burusn ukul, 2008, Maron 2009, Sabourdy 2009, LMM data). It has not been identified in large population studies. It was shown to alter splicing of the LAMP2 mRNA, resu lting in a frameshift and subsequent premature termination in exon 8 (Arad 2005, Sabourdy 2009). This variant has been identified in ClinVar (Variant ID: 9982). Loss of function of the LAMP2 gene is an established disease mechanism and is t ypically associated with Danon disease. In summary, this variant meets criteria to be classified as pathogenic. -

Cardiovascular phenotype Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Mar 19, 2021

The c.928G>A pathogenic mutation (also known as p.V310I), located in coding exon 7 of the LAMP2 gene, results from a G to A substitution at nucleotide position 928. The amino acid change results in valine to isoleucine at codon 310, an amino acid with highly similar properties. However, this change occurs in the last base pair of coding exon 7, which makes it likely to have some effect on normal mRNA splicing. This alteration has been reported de novo in a subject with hypertrophic cardiomyopathy (HCM) and Danon disease (Arad M et al. N Engl J Med, 2005 Jan;352:362-72). In addition, this mutation has been reported in HCM cohorts, subjects with Danon disease as well as other subjects with features of LAMP2-related disease (Sabourdy F et al. Muscle Nerve, 2009 Jun;39:837-44; Alfares AA et al. Genet Med, 2015 Nov;17:880-8; Walsh R et al. Genet Med, 2017 02;19:192-203; Gourzi P et al. Eur J Med Genet, 2019 Jan;62:77-80). This nucleotide position is highly conserved in available vertebrate species. In silico splice site analysis predicts that this alteration will weaken the native splice donor site. In addition, as a missense substitution this is predicted to be tolerated by in silico analysis. Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.085
CardioboostCm	Uncertain	0.76
BayesDel_addAF	Benign	-0.018	T
BayesDel_noAF	Benign	-0.26
CADD	Uncertain	24
DANN	Uncertain	0.99
DEOGEN2	Benign	0.21	.;T;.
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Benign	0.84	T;D;T
M_CAP	Uncertain	0.26	D
MetaRNN	Pathogenic	0.89	D;D;D
MetaSVM	Benign	-0.84	T
MutationAssessor	Uncertain	2.6	M;M;M
MutationTaster	Benign	0.31	A;A;A;A;A
PrimateAI	Benign	0.39	T
PROVEAN	Benign	-0.74	N;N;N
REVEL	Benign	0.19
Sift	Benign	0.25	T;T;T
Sift4G	Benign	0.20	T;T;T
Polyphen		0.071, 0.94	.;B;P
Vest4		0.69
MutPred		0.82		Gain of sheet (P = 0.0827);Gain of sheet (P = 0.0827);Gain of sheet (P = 0.0827);
MVP		0.88
MPC		0.51
ClinPred		0.88	D
GERP RS		5.2
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.29
gMVP		0.16

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.99
SpliceAI score (max)		0.81		Details are displayed if max score is > 0.2
DS_DL_spliceai		0.81		Position offset: 0

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

Publications

LitVar

Other links and lift over

dbSNP: rs104894858; hg19: chrX-119576454; COSMIC: COSV52355486;