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
Consequence
NM_002294.3 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Uncertain_significance. Variant got 2 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
LAMP2 | NM_002294.3 | c.610A>C | p.Thr204Pro | missense_variant | Exon 5 of 9 | ENST00000200639.9 | NP_002285.1 | |
LAMP2 | NM_001122606.1 | c.610A>C | p.Thr204Pro | missense_variant | Exon 5 of 9 | NP_001116078.1 | ||
LAMP2 | NM_013995.2 | c.610A>C | p.Thr204Pro | missense_variant | Exon 5 of 9 | NP_054701.1 |
Ensembl
Frequencies
GnomAD3 genomes Cov.: 23
GnomAD4 exome Cov.: 30
GnomAD4 genome Cov.: 23
ClinVar
Submissions by phenotype
not specified Uncertain:1
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
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:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at