X-120455477-C-T

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 0P and 4B. BS2

The NM_002294.3(LAMP2):c.277G>A(p.Gly93Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000157 in 1,207,391 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 6 hemizygotes in GnomAD. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.000018 ( 0 hom., 2 hem., cov: 21)

Exomes 𝑓: 0.000016 ( 0 hom. 4 hem. )

Consequence

LAMP2
NM_002294.3 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3B:1

Conservation

PhyloP100: 1.49

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]

LAMP2 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -4 ACMG points.

BS2

High Hemizygotes in GnomAd at 2 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE
LAMP2	NM_002294.3 linkuse as main transcript	c.277G>A	p.Gly93Arg	missense_variant	3/9	ENST00000200639.9
LAMP2	NM_001122606.1 linkuse as main transcript	c.277G>A	p.Gly93Arg	missense_variant	3/9
LAMP2	NM_013995.2 linkuse as main transcript	c.277G>A	p.Gly93Arg	missense_variant	3/9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
LAMP2	ENST00000200639.9 linkuse as main transcript	c.277G>A	p.Gly93Arg	missense_variant	3/9	1	NM_002294.3	P3	P13473-1
LAMP2	ENST00000434600.6 linkuse as main transcript	c.277G>A	p.Gly93Arg	missense_variant	3/9	1		A1	P13473-3
LAMP2	ENST00000371335.4 linkuse as main transcript	c.277G>A	p.Gly93Arg	missense_variant	3/9	1		A1	P13473-2
LAMP2	ENST00000706600.1 linkuse as main transcript	c.277G>A	p.Gly93Arg	missense_variant	3/9

Frequencies

GnomAD3 genomes

AF:

0.0000180

AC:

AN:

110904

Hom.:

Cov.:

AF XY:

0.0000604

AC XY:

AN XY:

33132

show subpopulations

Gnomad AFR

AF:

0.0000657

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000436

AC:

AN:

183481

Hom.:

AF XY:

0.00

AC XY:

AN XY:

67925

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000365

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000216

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000488

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000155

AC:

AN:

1096487

Hom.:

Cov.:

AF XY:

0.0000111

AC XY:

AN XY:

361861

show subpopulations

Gnomad4 AFR exome

AF:

0.000114

Gnomad4 AMR exome

AF:

0.0000568

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000994

Gnomad4 SAS exome

AF:

0.0000185

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000714

Gnomad4 OTH exome

AF:

0.0000434

GnomAD4 genome

AF:

0.0000180

AC:

AN:

110904

Hom.:

Cov.:

AF XY:

0.0000604

AC XY:

AN XY:

33132

show subpopulations

Gnomad4 AFR

AF:

0.0000657

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.0000113

ExAC

AF:

0.0000412

AC:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:3Benign:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Danon disease

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Jul 19, 2023

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. Studies have shown that this missense change alters LAMP2 gene expression (PMID: 31464081). 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. ClinVar contains an entry for this variant (Variation ID: 179562). This missense change has been observed in individual(s) with clinical features of Danon disease (PMID: 31464081). This variant is present in population databases (rs727504953, gnomAD 0.02%). This sequence change replaces glycine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 93 of the LAMP2 protein (p.Gly93Arg). -

Cardiomyopathy

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario

Mar 16, 2021

- -

Cardiovascular phenotype

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Feb 16, 2022

The p.G93R variant (also known as c.277G>A), located in coding exon 3 of the LAMP2 gene, results from a G to A substitution at nucleotide position 277. The glycine at codon 93 is replaced by arginine, an amino acid with dissimilar properties. This variant has been detected in individuals with hypertrophic cardiomyopathy; however, co-occurring cardiac variants were also reported and/or clinical details were limited in most cases (Xu J et al. Mol Genet Genomic Med, 2019 10;7:e00941; Kresin N et al. Front Physiol, 2019 Mar;10:239; Harper AR et al. Nat Genet, 2021 02;53:135-142). Based on data from gnomAD, the A allele has an overall frequency of 0.0044% (8/183481) total alleles studied, with 0 hemizygotes observed. The highest observed frequency was 0.0216% (3/13860) of East Asian alleles. This amino acid position is well conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -

not specified

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Mar 04, 2014

Gly93Arg in exon 3 of LAMP2: This variant is not expected to have clinical signi ficance due to a lack of conservation across species, including mammals. Of note , marmoset, squirrel monkey, tree shrew, guinea pig, and rat have an arginine (A rg) at this position. Furthermore, nearly all disease-causing variants in LAMP2 have been truncating loss of function variants, while this is a missense variant . Gly93Arg in exon 3 of LAMP2 (allele frequency = n/a) -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.15

CardioboostCm

Benign

0.0040

BayesDel_addAF

Benign

-0.46

BayesDel_noAF

Benign

-0.60

Cadd

Benign

Dann

Benign

0.95

FATHMM_MKL

Benign

0.55

LIST_S2

Benign

0.78

T;T;T

M_CAP

Benign

0.012

MetaRNN

Uncertain

0.66

D;D;D

MetaSVM

Benign

-1.0

MutationAssessor

Uncertain

2.6

M;M;M

MutationTaster

Benign

0.99

D;D;D;D;D

PrimateAI

Benign

0.34

PROVEAN

Pathogenic

-6.8

D;D;D

REVEL

Benign

0.13

Sift

Benign

0.039

D;D;D

Sift4G

Uncertain

0.029

D;D;D

Polyphen

0.63, 0.88

.;P;P

Vest4

0.36

MutPred

0.81

Gain of MoRF binding (P = 0.056);Gain of MoRF binding (P = 0.056);Gain of MoRF binding (P = 0.056);

MVP

0.31

MPC

0.32

ClinPred

0.15

GERP RS

1.7

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.24

gMVP

0.92

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.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over