X-120446345-T-C
Variant summary
Our verdict is Likely benign. Variant got -4 ACMG points: 2P and 6B. PM1BP4_ModerateBS2
The NM_002294.3(LAMP2):āc.824A>Gā(p.Asn275Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000914 in 1,203,555 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 5 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (ā ā ). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. N275H) has been classified as Uncertain significance.
Frequency
Consequence
NM_002294.3 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_benign. Variant got -4 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
LAMP2 | NM_002294.3 | c.824A>G | p.Asn275Ser | missense_variant | 6/9 | ENST00000200639.9 | |
LAMP2 | NM_001122606.1 | c.824A>G | p.Asn275Ser | missense_variant | 6/9 | ||
LAMP2 | NM_013995.2 | c.824A>G | p.Asn275Ser | missense_variant | 6/9 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
LAMP2 | ENST00000200639.9 | c.824A>G | p.Asn275Ser | missense_variant | 6/9 | 1 | NM_002294.3 | P3 |
Frequencies
GnomAD3 genomes AF: 0.0000628 AC: 7AN: 111493Hom.: 0 Cov.: 22 AF XY: 0.000119 AC XY: 4AN XY: 33665
GnomAD3 exomes AF: 0.0000109 AC: 2AN: 183431Hom.: 0 AF XY: 0.0000147 AC XY: 1AN XY: 67881
GnomAD4 exome AF: 0.00000366 AC: 4AN: 1092062Hom.: 0 Cov.: 29 AF XY: 0.00000280 AC XY: 1AN XY: 357568
GnomAD4 genome AF: 0.0000628 AC: 7AN: 111493Hom.: 0 Cov.: 22 AF XY: 0.000119 AC XY: 4AN XY: 33665
ClinVar
Submissions by phenotype
not specified Uncertain:2
Uncertain significance, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Dec 13, 2023 | Variant summary: LAMP2 c.824A>G (p.Asn275Ser) results in a conservative amino acid change located in the Lysosome-associated membrane glycoprotein 2-like, luminal domains (IPR048528) of the encoded protein sequence. Five of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 9.1e-06 in 1203555 control chromosomes including 5 hemizygotes suggesting a benign role. c.824A>G has been reported in the literature in individuals affected with Cardiomyopathy (Walsh_2017). These report(s) do not provide unequivocal conclusions about association of the variant with Danon Disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publication have been ascertained in the context of this evaluation (PMID: 27532257). Two submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. All submitters classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as VUS-possibly benign. - |
Uncertain significance, no assertion criteria provided | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | May 04, 2009 | - - |
Danon disease Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Oct 23, 2023 | This sequence change replaces asparagine, which is neutral and polar, with serine, which is neutral and polar, at codon 275 of the LAMP2 protein (p.Asn275Ser). This variant is present in population databases (rs397516747, gnomAD 0.02%), including at least one homozygous and/or hemizygous individual. This missense change has been observed in individual(s) with hypertrophic cardiomyopathy (PMID: 27532257). ClinVar contains an entry for this variant (Variation ID: 44438). 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. 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
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Feb 01, 2022 | Observed in patients with HCM referred for genetic testing at GeneDx and in the published literature (Walsh et al., 2017); however, one individual harbored additional pathogenic variants in other genes associated with cardiomyopathy; In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 27532257) - |
Cardiovascular phenotype Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Aug 08, 2022 | The c.824A>G (p.N275S) alteration is located in exon 6 (coding exon 6) of the LAMP2 gene. This alteration results from a A to G substitution at nucleotide position 824, causing the asparagine (N) at amino acid position 275 to be replaced by a serine (S). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at