rs876657845

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 4P and 2B. PM1PM2BP4_Moderate

The NM_002294.3(LAMP2):​c.610A>C​(p.Thr204Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. T204I) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 23)

Consequence

LAMP2
NM_002294.3 missense

Scores

2
16

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:2

Conservation

PhyloP100: 0.669
Variant links:
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]

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 2 ACMG points.

PM1
In a glycosylation_site O-linked (GalNAc...) threonine (size 0) in uniprot entity LAMP2_HUMAN
PM2
Very rare variant in population databases, with high coverage;
BP4
Computational evidence support a benign effect (MetaRNN=0.16236565).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
LAMP2NM_002294.3 linkc.610A>C p.Thr204Pro missense_variant Exon 5 of 9 ENST00000200639.9 NP_002285.1 P13473-1
LAMP2NM_001122606.1 linkc.610A>C p.Thr204Pro missense_variant Exon 5 of 9 NP_001116078.1 P13473-3
LAMP2NM_013995.2 linkc.610A>C p.Thr204Pro missense_variant Exon 5 of 9 NP_054701.1 P13473-2

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
LAMP2ENST00000200639.9 linkc.610A>C p.Thr204Pro missense_variant Exon 5 of 9 1 NM_002294.3 ENSP00000200639.4 P13473-1

Frequencies

GnomAD3 genomes
Cov.:
23
GnomAD4 exome
Cov.:
30
GnomAD4 genome
Cov.:
23

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:2
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

not specified Uncertain:1
Jul 16, 2015
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

The p.Thr204Pro variant in LAMP2 has not been previously reported in individuals with cardiomyopathy or in large population studies. While computational predict ion tools and conservation analysis do not provide strong support for or against an impact to the protein, pathogenic missense variants in LAMP2 are exceedingly rare (nearly all the disease-causing variants cause a truncated or absent prote in). In summary, the clinical significance of the p.Thr204Pro variant is uncerta in. -

Danon disease Uncertain:1
Mar 12, 2024
Labcorp Genetics (formerly Invitae), Labcorp
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

This sequence change replaces threonine, which is neutral and polar, with proline, which is neutral and non-polar, at codon 204 of the LAMP2 protein (p.Thr204Pro). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with LAMP2-related conditions. ClinVar contains an entry for this variant (Variation ID: 228787). 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 not expected to disrupt LAMP2 protein function with a negative predictive value of 80%. 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. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.080
CardioboostCm
Benign
0.0027
BayesDel_addAF
Benign
-0.24
T
BayesDel_noAF
Benign
-0.59
CADD
Benign
16
DANN
Uncertain
0.99
DEOGEN2
Benign
0.23
.;T;.
FATHMM_MKL
Uncertain
0.89
D
LIST_S2
Benign
0.59
T;T;T
M_CAP
Benign
0.021
T
MetaRNN
Benign
0.16
T;T;T
MetaSVM
Benign
-1.1
T
MutationAssessor
Benign
1.9
L;L;L
PrimateAI
Benign
0.36
T
PROVEAN
Benign
-1.7
N;N;N
REVEL
Benign
0.083
Sift
Benign
0.22
T;T;T
Sift4G
Benign
0.10
T;T;T
Polyphen
0.053, 0.019
.;B;B
Vest4
0.20
MutPred
0.35
Loss of glycosylation at T204 (P = 0.0143);Loss of glycosylation at T204 (P = 0.0143);Loss of glycosylation at T204 (P = 0.0143);
MVP
0.62
MPC
0.39
ClinPred
0.38
T
GERP RS
3.0
Varity_R
0.38
gMVP
0.82

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs876657845; hg19: chrX-119581827; API