19-11113306-C-A
Variant summary
Our verdict is Pathogenic. The variant received 21 ACMG points: 21P and 0B. PS1_Very_StrongPM1PM2PM5PP2PP3_StrongPP5_Moderate
The NM_000527.5(LDLR):c.1215C>A(p.Asn405Lys) 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 pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Likely pathogenic in ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. N405S) has been classified as Likely pathogenic.
Frequency
Consequence
NM_000527.5 missense
Scores
Clinical Significance
Conservation
Publications
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ACMG classification
Our verdict: Pathogenic. The variant received 21 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
LDLR | NM_000527.5 | c.1215C>A | p.Asn405Lys | missense_variant | Exon 9 of 18 | ENST00000558518.6 | NP_000518.1 |
Ensembl
Frequencies
GnomAD3 genomes Cov.: 29
GnomAD4 exome Cov.: 33
GnomAD4 genome Cov.: 29
ClinVar
Submissions by phenotype
Familial hypercholesterolemia Pathogenic:1
This sequence change replaces asparagine, which is neutral and polar, with lysine, which is basic and polar, at codon 405 of the LDLR protein (p.Asn405Lys). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with familial hypercholesterolemia (PMID: 29576406; Invitae). 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 LDLR protein function. For these reasons, this variant has been classified as Pathogenic. -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at