rs727504600

Variant names:

• chrX-120456712-CA-C
• rs727504600
• NM_002294.3:c.121delT

Variant summary

Our verdict is Pathogenic. The variant received 12 ACMG points: 12P and 0B. PVS1 PM2 PP5_Moderate

The NM_002294.3(LAMP2):​c.121delT​(p.Cys41AlafsTer8) variant causes a frameshift change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic (★). Synonymous variant affecting the same amino acid position (i.e. C41C) has been classified as Likely benign. Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: not found (cov: 22)
  • Exomes 𝑓: 0.0 (0 hom. 0 hem.)
  • Failed GnomAD Quality Control
• Consequence: LAMP2 NM_002294.3 frameshift
• Clinical Significance: Pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 5.70
• Publications: 2 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: Pathogenic. The variant received 12 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant X-120456712-CA-C is Pathogenic according to our data. Variant chrX-120456712-CA-C is described in ClinVar as [Pathogenic]. Clinvar id is 179062.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
LAMP2	NM_002294.3	c.121delT	p.Cys41AlafsTer8	frameshift_variant	Exon 2 of 9	ENST00000200639.9	NP_002285.1
LAMP2	NM_001122606.1	c.121delT	p.Cys41AlafsTer8	frameshift_variant	Exon 2 of 9		NP_001116078.1
LAMP2	NM_013995.2	c.121delT	p.Cys41AlafsTer8	frameshift_variant	Exon 2 of 9		NP_054701.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
LAMP2	ENST00000200639.9	c.121delT	p.Cys41AlafsTer8	frameshift_variant	Exon 2 of 9	1	NM_002294.3	ENSP00000200639.4
LAMP2	ENST00000434600.6	c.121delT	p.Cys41AlafsTer8	frameshift_variant	Exon 2 of 9	1		ENSP00000408411.2
LAMP2	ENST00000371335.4	c.121delT	p.Cys41AlafsTer8	frameshift_variant	Exon 2 of 9	1		ENSP00000360386.4
LAMP2	ENST00000706600.1	c.121delT	p.Cys41AlafsTer8	frameshift_variant	Exon 2 of 9			ENSP00000516464.1

Frequencies

GnomAD3 genomes Cov.: 22

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1080686 Hom.: 0 Cov.: 24 AF XY: 0.00 AC XY: 0 AN XY: 349648

African (AFR) AF: 0.00 AC: 0 AN: 26137

American (AMR) AF: 0.00 AC: 0 AN: 35051

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19203

East Asian (EAS) AF: 0.00 AC: 0 AN: 29989

South Asian (SAS) AF: 0.00 AC: 0 AN: 52164

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 40142

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3347

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 829324

Other (OTH) AF: 0.00 AC: 0 AN: 45329

GnomAD4 genome Cov.: 22

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

Danon disease Pathogenic:1

Aug 09, 2013

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The Cys41fs variant in LAMP2 has not been reported in individuals with cardiomyo pathy or Danon disease or in large population studies. This frameshift variant i s predicted to alter the protein?s amino acid sequence beginning at position 41 and lead to a premature termination codon 8 amino acids downstream. This alterat ion is then predicted to lead to a truncated or absent protein. Loss of function of the LAMP2 gene is an established disease mechanism in males with Danon disea se. In summary, this variant meets our criteria to be classified as pathogenic ( http://pcpgm.partners.org/LMM) based upon the predicted impact to the protein. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
PhyloP100		5.7
Mutation Taster		=0/200	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.080		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: rs727504600; hg19: chrX-119590567;