rs879254809
Variant summary
Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2PP3
This summary comes from the ClinGen Evidence Repository: The NM_000527.5(LDLR):c.1154T>C (p.Leu385Pro) variant is classified as Uncertain significance - insufficient evidence for Familial Hypercholesterolemia by applying evidence codes (PM2 and PP3) 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:PM2: This variant is absent from gnomAD (gnomAD v2.1.1).PP3: REVEL = 0.787. LINK:https://erepo.genome.network/evrepo/ui/classification/CA404083801/MONDO:0007750/013
Frequency
Consequence
NM_000527.5 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Uncertain_significance. Variant got 3 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
LDLR | NM_000527.5 | c.1154T>C | p.Leu385Pro | missense_variant | 8/18 | ENST00000558518.6 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
LDLR | ENST00000558518.6 | c.1154T>C | p.Leu385Pro | missense_variant | 8/18 | 1 | NM_000527.5 | P3 |
Frequencies
GnomAD3 genomes ? Cov.: 31
GnomAD4 exome AF: 6.84e-7 AC: 1AN: 1461514Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0AN XY: 727046
GnomAD4 genome ? Cov.: 31
ClinVar
Submissions by phenotype
Hypercholesterolemia, familial, 1 Pathogenic:1Uncertain:1
Pathogenic, no assertion criteria provided | research | Laboratorium voor Moleculaire Diagnostiek Experimentele Vasculaire Geneeskunde, Academisch Medisch Centrum | - | - - |
Uncertain significance, reviewed by expert panel | curation | ClinGen Familial Hypercholesterolemia Variant Curation Expert Panel | Apr 28, 2023 | The NM_000527.5(LDLR):c.1154T>C (p.Leu385Pro) variant is classified as Uncertain significance - insufficient evidence for Familial Hypercholesterolemia by applying evidence codes (PM2 and PP3) 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: PM2: This variant is absent from gnomAD (gnomAD v2.1.1). PP3: REVEL = 0.787. - |
Cardiovascular phenotype Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Aug 05, 2020 | The p.L385P variant (also known as c.1154T>C), located in coding exon 8 of the LDLR gene, results from a T to C substitution at nucleotide position 1154. The leucine at codon 385 is replaced by proline, an amino acid with similar properties, and is located in an EGF-like domain. Other variants affecting this codon (p.L385R, c.1154T>G and p.L385V, c.1153C>G) have been detected in hypercholesterolemia cohorts (Kotze MJ et al. Clin. Genet., 1998 Jul;54:74-8; Marduel M et al. Hum. Mutat., 2010 Nov;31:E1811-24). This amino acid position is not well 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