rs730880344

Variant names:

• chrX-120456704-C-CAT
• rs730880344
• NM_002294.3:c.128_129dupAT

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PVS1 PM2 PP5_Moderate

The NM_002294.3(LAMP2):​c.128_129dupAT​(p.Ala44MetfsTer6) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Likely pathogenic (★). Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 22)
• Consequence: LAMP2 NM_002294.3 frameshift
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 2.38

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 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-120456704-C-CAT is Pathogenic according to our data. Variant chrX-120456704-C-CAT is described in ClinVar as [Likely_pathogenic]. Clinvar id is 177994.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.128_129dupAT	p.Ala44MetfsTer6	frameshift_variant	Exon 2 of 9	ENST00000200639.9	NP_002285.1
LAMP2	NM_001122606.1	c.128_129dupAT	p.Ala44MetfsTer6	frameshift_variant	Exon 2 of 9		NP_001116078.1
LAMP2	NM_013995.2	c.128_129dupAT	p.Ala44MetfsTer6	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.128_129dupAT	p.Ala44MetfsTer6	frameshift_variant	Exon 2 of 9	1	NM_002294.3	ENSP00000200639.4
LAMP2	ENST00000434600.6	c.128_129dupAT	p.Ala44MetfsTer6	frameshift_variant	Exon 2 of 9	1		ENSP00000408411.2
LAMP2	ENST00000371335.4	c.128_129dupAT	p.Ala44MetfsTer6	frameshift_variant	Exon 2 of 9	1		ENSP00000360386.4
LAMP2	ENST00000706600.1	c.128_129dupAT	p.Ala44MetfsTer6	frameshift_variant	Exon 2 of 9			ENSP00000516464.1

Frequencies

GnomAD3 genomes Cov.: 22

GnomAD4 exome Cov.: 24

GnomAD4 genome Cov.: 22

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

Hypertrophic cardiomyopathy;C0878677:Danon disease Pathogenic:1

Feb 23, 2012

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The Ala44fs variant in LAMP2 has not been previously reported in the literature or identified by our laboratory. The Ala44fs variant in LAMP2 is predicted to ca use a frameshift, which alters the protein's amino acid sequence beginning at co don 44 and leads to a premature stop codon six amino acids downstream. This alt eration is then predicted to lead to a truncated or absent protein. Loss of fun ction is an established mechanism of disease for the LAMP2 gene, which makes it highly likely that the Ala44fs variant is pathogenic. Pathogenic variants in LAM P2 have been associated with Danon disease. -

Computational scores

Source: dbNSFP v4.3

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs730880344; hg19: chrX-119590559;