X-120449006-G-T
Variant summary
Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2PP3_Moderate
The NM_002294.3(LAMP2):c.520C>A(p.Gln174Lys) variant causes a missense change. The variant allele was found at a frequency of 0.00000166 in 1,207,951 control chromosomes in the GnomAD database, with no homozygous occurrence. There are no hemizygote samples in GnomAD. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar 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 4 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
LAMP2 | NM_002294.3 | c.520C>A | p.Gln174Lys | missense_variant | Exon 4 of 9 | ENST00000200639.9 | NP_002285.1 | |
LAMP2 | NM_001122606.1 | c.520C>A | p.Gln174Lys | missense_variant | Exon 4 of 9 | NP_001116078.1 | ||
LAMP2 | NM_013995.2 | c.520C>A | p.Gln174Lys | missense_variant | Exon 4 of 9 | NP_054701.1 |
Ensembl
Frequencies
GnomAD3 genomes AF: 0.00000893 AC: 1AN: 111993Hom.: 0 Cov.: 23 AF XY: 0.00 AC XY: 0AN XY: 34171
GnomAD4 exome AF: 9.12e-7 AC: 1AN: 1095958Hom.: 0 Cov.: 29 AF XY: 0.00 AC XY: 0AN XY: 361394
GnomAD4 genome AF: 0.00000893 AC: 1AN: 111993Hom.: 0 Cov.: 23 AF XY: 0.00 AC XY: 0AN XY: 34171
ClinVar
Submissions by phenotype
Danon disease Uncertain:1
This sequence change replaces glutamine, which is neutral and polar, with lysine, which is basic and polar, at codon 174 of the LAMP2 protein (p.Gln174Lys). 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: 855949). 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 expected to disrupt LAMP2 protein function with a positive 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. -
not provided Uncertain:1
Not observed in large population cohorts (Lek et al., 2016); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; Has not been previously published as pathogenic or benign to our knowledge -
Cardiovascular phenotype Uncertain:1
The p.Q174K variant (also known as c.520C>A), located in coding exon 4 of the LAMP2 gene, results from a C to A substitution at nucleotide position 520. The glutamine at codon 174 is replaced by lysine, an amino acid with similar properties. This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at