rs397516748

Variant names:

• chrX-120446327-T-C
• rs397516748
• NM_002294.3:c.842A>G

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_002294.3(LAMP2):​c.842A>G​(p.Tyr281Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000915 in 1,093,450 control chromosomes in the GnomAD database, with no homozygous occurrence. There are no hemizygote samples in GnomAD. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: not found (cov: 22)
  • Exomes 𝑓: 9.1e-7 (0 hom. 0 hem.)
• Consequence: LAMP2 NM_002294.3 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:3
• Conservation: PhyloP100: 0.352
• Publications: 3 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: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
LAMP2	NM_002294.3	c.842A>G	p.Tyr281Cys	missense_variant	Exon 6 of 9	ENST00000200639.9	NP_002285.1
LAMP2	NM_001122606.1	c.842A>G	p.Tyr281Cys	missense_variant	Exon 6 of 9		NP_001116078.1
LAMP2	NM_013995.2	c.842A>G	p.Tyr281Cys	missense_variant	Exon 6 of 9		NP_054701.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
LAMP2	ENST00000200639.9	c.842A>G	p.Tyr281Cys	missense_variant	Exon 6 of 9	1	NM_002294.3	ENSP00000200639.4

Frequencies

GnomAD3 genomes Cov.: 22

GnomAD4 exome AF: 9.15e-7 AC: 1 AN: 1093450 Hom.: 0 Cov.: 29 AF XY: 0.00 AC XY: 0 AN XY: 358954

African (AFR) AF: 0.0000380 AC: 1 AN: 26338

American (AMR) AF: 0.00 AC: 0 AN: 35199

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19349

East Asian (EAS) AF: 0.00 AC: 0 AN: 30181

South Asian (SAS) AF: 0.00 AC: 0 AN: 54045

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 40518

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4127

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 837753

Other (OTH) AF: 0.00 AC: 0 AN: 45940

GnomAD4 genome Cov.: 22

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Uncertain:1

Dec 08, 2011

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant classified as Uncertain Significance - Favor Benign. The Tyr281Cys varia nt (LAMP2) has not been previously reported. It has been detected by our labora tory in 1 out of >1250 Caucasian probands tested. This individual had DCM + mus cle weakness and carried a likely pathogenic variant in the LMNA gene. A reporte d paternal family history of disease is be inconsistent with X-linked inheritanc e and argues against a pathogenic role of the Tyr281Cys variant. In addition, ty rosine (Tyr) at position 281 is not conserved in mammals and lower species, sugg esting that a change at this position may be tolerated. Computational prediction s are mixed on the predicted impact to the protein (AlignGVGD = benign and SIFT = pathogenic), though the accuracy of these tools is unknown. Importantly, path ogenic missense variants are very rare in the LAMP2 gene (most disease causing v ariants cause a loss of function). In summary, this variant is less likely disea se causing and is more likely a modifier or benign. However, additional evidenc e is needed to determine this with certainty. -

Danon disease Uncertain:1

May 22, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt LAMP2 protein function. ClinVar contains an entry for this variant (Variation ID: 44439). This missense change has been observed in individual(s) with dilated cardiomyopathy (PMID: 27532257). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces tyrosine, which is neutral and polar, with cysteine, which is neutral and slightly polar, at codon 281 of the LAMP2 protein (p.Tyr281Cys). -

Cardiovascular phenotype Uncertain:1

Jun 06, 2022

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.842A>G (p.Y281C) alteration is located in exon 6 (coding exon 6) of the LAMP2 gene. This alteration results from a A to G substitution at nucleotide position 842, causing the tyrosine (Y) at amino acid position 281 to be replaced by a cysteine (C). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.34
CardioboostCm	Benign	0.013
BayesDel_addAF	Benign	-0.046	T
BayesDel_noAF	Benign	-0.30
CADD	Benign	23
DANN	Uncertain	0.99
DEOGEN2	Benign	0.32	.;T;.
FATHMM_MKL	Benign	0.35	N
LIST_S2	Uncertain	0.91	D;D;D
M_CAP	Benign	0.040	D
MetaRNN	Uncertain	0.67	D;D;D
MetaSVM	Benign	-0.93	T
MutationAssessor	Uncertain	2.6	M;M;M
PhyloP100		0.35
PrimateAI	Uncertain	0.58	T
PROVEAN	Uncertain	-3.3	D;D;D
REVEL	Benign	0.20
Sift	Uncertain	0.028	D;D;D
Sift4G	Uncertain	0.012	D;T;D
Polyphen		1.0, 0.99	.;D;D
Vest4		0.67
MutPred		0.43		Gain of methylation at K280 (P = 0.0139);Gain of methylation at K280 (P = 0.0139);Gain of methylation at K280 (P = 0.0139);
MVP		0.79
MPC		0.93
ClinPred		0.89	D
GERP RS		1.2
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.28
gMVP		0.45
Mutation Taster		=91/9	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

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

Other links and lift over

dbSNP: rs397516748; hg19: chrX-119580182;