ClinGen Dosage Sensitivity Curation Page

LAMP2

  • Curation Status: Complete

Location Information

Select assembly: (NC_000023.10) (NC_000023.11)
  • Haploinsufficiency score: 3
  • Strength of Evidence (disclaimer): Sufficient evidence for dosage pathogenicity
  • Haploinsufficiency Phenotype: DANON DISEASE
Evidence for haploinsufficiency phenotype
PubMed ID Description
20173215 Yang (2010): A report of three male patients with Danon disease who had intragenic deletions in LAMP2. Parental studies were not available for two patients and one deletion was found to be de novo.
19588270 Regelsberg (2009): A report of a male patient with Danon disease who had a de novo frameshift mutation in LAMP2.
19057086 Dougu (2009): A report of a frameshift mutation in LAMP2 found in a boy with Danon disease as well as his mother and two sisters who have cardiomyopathy. The authors also provide a table listing multiple loss-of-function mutations that had been reported previously.
27145725 Sugie et al (2016) describe a 15 year old girl with Danon disease who presented with early onset of hypertrophic cardiomyopathy and mild intellectual disability. She had a de novo novel mutation, c.749C > A (p.Ser250X), in the LAMP2 gene, and her muscles showed decreased LAMP?2 expression. There are also many more reports of de novo and maternally inherited loss of function LAMP2 variants in the literature associated with Danon disease.
10972294 Nishino et al. (2000) report ten unrelated patients with Danon disease and variants in LAMP2, including nonsense, frameshift, and exon-skipping variants. At least 6 of these variants were demonstrated to result in complete LAMP-2 deficiency by Western blot analysis on frozen skeletal muscle specimens from the patients.
16565504

Haploinsufficiency phenotype comments:

Loss of function mutations in LAMP2 cause Danon disease in males (OMIM 300257). Danon disease is a multisystem condition with predominant involvement of the heart, skeletal muscles, and retina, with overlying cognitive dysfunction. The clinical features in females are broader and more variable. Females are more likely to have dilated cardiomyopathy, with a smaller proportion requiring heart transplantation compared to affected males. Cardiac conduction abnormalities, skeletal muscle weakness, mild cognitive impairment, and pigmentary retinopathy are variably seen in affected females.

The loss-of-function and triplosensitivity ratings for genes on the X chromosome are made in the context of a male genome to account for the effects of hemizygous duplications or nullizygous deletions. In contrast, disruption of some genes on the X chromosome causes male lethality and the ratings of dosage sensitivity instead take into account the phenotype in female individuals. Factors that may affect the severity of phenotypes associated with X-linked disorders include the presence of variable copies of the X chromosome (i.e. 47,XXY or 45,X) and skewed X-inactivation in females.

  • Triplosensitivity score: 0
  • Strength of Evidence (disclaimer): No evidence for dosage pathogenicity

The loss-of-function and triplosensitivity ratings for genes on the X chromosome are made in the context of a male genome to account for the effects of hemizygous duplications or nullizygous deletions. In contrast, disruption of some genes on the X chromosome causes male lethality and the ratings of dosage sensitivity instead take into account the phenotype in female individuals. Factors that may affect the severity of phenotypes associated with X-linked disorders include the presence of variable copies of the X chromosome (i.e. 47,XXY or 45,X) and skewed X-inactivation in females.