rs879254879
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PM1PM2PM5PP3_StrongPP5_Very_Strong
The NM_000527.5(LDLR):c.1361C>A(p.Thr454Asn) variant causes a missense, splice region change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely pathogenic (★★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. T454I) has been classified as Likely pathogenic.
Frequency
Consequence
NM_000527.5 missense, splice_region
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 18 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
LDLR | NM_000527.5 | c.1361C>A | p.Thr454Asn | missense_variant, splice_region_variant | 10/18 | ENST00000558518.6 | |
MIR6886 | NR_106946.1 | downstream_gene_variant |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
LDLR | ENST00000558518.6 | c.1361C>A | p.Thr454Asn | missense_variant, splice_region_variant | 10/18 | 1 | NM_000527.5 | P3 | |
MIR6886 | ENST00000619864.1 | downstream_gene_variant |
Frequencies
GnomAD3 genomes ? Cov.: 31
GnomAD4 exome Cov.: 38
GnomAD4 genome ? Cov.: 31
ClinVar
Submissions by phenotype
Hypercholesterolemia, familial, 1 Pathogenic:3
Likely pathogenic, criteria provided, single submitter | literature only | LDLR-LOVD, British Heart Foundation | Mar 25, 2016 | - - |
Likely pathogenic, criteria provided, single submitter | research | Fundacion Hipercolesterolemia Familiar | Mar 01, 2016 | - - |
Likely pathogenic, reviewed by expert panel | curation | ClinGen Familial Hypercholesterolemia Variant Curation Expert Panel | Jan 31, 2022 | The NM_000527.5(LDLR):c.1361C>A (p.Thr454Asn) variant is classified as Likely pathogenic for Familial Hypercholesterolemia by applying evidence codes PS3, PM2 and PP4 as defined by the ClinGen Familial Hypercholesterolemia Expert Panel LDLR-specific variant curation guidelines (https://doi.org/10.1016/j.gim.2021.09.012). The supporting evidence is as follows: PS3 - Level 1 FS: Etxebarria et al. 2015 (PMID 25378237): Heterologous cells (CHO) with FACS - results: 65% LDL-LDLR binding, uptake and cell surface LDLR --- activity is below 70% of wild-type, so PS3 is met. PM2 - This variant is absent from gnomAD (gnomAD v2.1.1), so PM2 is met. PP4 - variant meets PM2 and was identified in 1 index case with MEDPED clinical criteria of FH (45 year old female with TC 398mg/dl) from PMID: 19007590 (Civeira et al. 2008), Spain; so PP4 is met. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at