chrX-120442599-C-G

Position:

• chrX-120442599-C-G

Variant summary

Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PM2 PM5 PP3_Strong PP5_Moderate

The NM_002294.3(LAMP2):​c.928G>C​(p.Val310Leu) variant causes a missense, splice region change. The variant was absent in control chromosomes in GnomAD project. 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. V310I) has been classified as Pathogenic.

• Frequency: Genomes: not found (cov: 22)
• Consequence: LAMP2 NM_002294.3 missense, splice_region
• Scores: Splicing: ADA: 1.000
• Clinical Significance: Pathogenic criteria provided, single submitter P:1
• 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 10 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-T is described in ClinVar as [Pathogenic]. Clinvar id is 9982.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 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-G is Pathogenic according to our data. Variant chrX-120442599-C-G is described in ClinVar as [Pathogenic]. Clinvar id is 1452436.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
LAMP2	NM_002294.3	c.928G>C	p.Val310Leu	missense_variant, splice_region_variant	7/9	ENST00000200639.9
LAMP2	NM_001122606.1	c.928G>C	p.Val310Leu	missense_variant, splice_region_variant	7/9
LAMP2	NM_013995.2	c.928G>C	p.Val310Leu	missense_variant, splice_region_variant	7/9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
LAMP2	ENST00000200639.9	c.928G>C	p.Val310Leu	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:1

Revision: criteria provided, single submitter

Submissions by phenotype

Danon disease Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Mar 22, 2021

For these reasons, this variant has been classified as Pathogenic. This variant disrupts the c.928G nucleotide in the LAMP2 gene. Other variant(s) that disrupt this nucleotide have been determined to be pathogenic (PMID: 16217705, 15673802, 29753918, 19373884, 29753918). This suggests that this nucleotide is clinically significant, and that variants that disrupt this position are likely to be disease-causing. Nucleotide substitutions within the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site, but this prediction has not been confirmed by published transcriptional studies. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. This variant has been observed in individual(s) with clinical features of Danon disease (Invitae). In at least one individual the variant was observed to be de novo. This variant is not present in population databases (ExAC no frequency). This sequence change replaces valine with leucine at codon 310 of the LAMP2 protein (p.Val310Leu). The valine residue is weakly conserved and there is a small physicochemical difference between valine and leucine. This variant also falls at the last nucleotide of exon 7, which is part of the consensus splice site for this exon. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.15
CardioboostCm	Uncertain	0.59
BayesDel_addAF	Benign	-0.22	T
BayesDel_noAF	Benign	-0.55
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Benign	0.26	.;T;.
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.90	D;D;D
M_CAP	Uncertain	0.27	D
MetaRNN	Uncertain	0.52	D;D;D
MetaSVM	Benign	-0.90	T
MutationAssessor	Uncertain	2.6	M;M;M
MutationTaster	Benign	0.63	D;D;N;N;N
PrimateAI	Benign	0.47	T
PROVEAN	Benign	-1.5	N;N;N
REVEL	Benign	0.17
Sift	Benign	0.19	T;T;T
Sift4G	Benign	0.30	T;T;T
Polyphen		0.16, 0.59	.;B;P
Vest4		0.34
MutPred		0.71		Loss of catalytic residue at V310 (P = 0.0154);Loss of catalytic residue at V310 (P = 0.0154);Loss of catalytic residue at V310 (P = 0.0154);
MVP		0.76
MPC		0.56
ClinPred		0.89	D
GERP RS		5.2
Varity_R		0.45
gMVP		0.28

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	1.0
SpliceAI score (max)		0.85		Details are displayed if max score is > 0.2
DS_DL_spliceai		0.85		Position offset: 0

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

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chrX-119576454;