chr19-11116892-C-T
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PM1PM2PM5PP3_StrongPP5_Very_Strong
The NM_000527.5(LDLR):c.1739C>T(p.Ser580Phe) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,808 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 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. S580C) has been classified as Uncertain significance.
Frequency
Consequence
NM_000527.5 missense
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.1739C>T | p.Ser580Phe | missense_variant | 12/18 | ENST00000558518.6 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
LDLR | ENST00000558518.6 | c.1739C>T | p.Ser580Phe | missense_variant | 12/18 | 1 | NM_000527.5 | P3 |
Frequencies
GnomAD3 genomes Cov.: 32
GnomAD3 exomes AF: 0.00000398 AC: 1AN: 251488Hom.: 0 AF XY: 0.00000736 AC XY: 1AN XY: 135918
GnomAD4 exome AF: 6.84e-7 AC: 1AN: 1461808Hom.: 0 Cov.: 35 AF XY: 0.00000138 AC XY: 1AN XY: 727204
GnomAD4 genome Cov.: 32
ClinVar
Submissions by phenotype
Hypercholesterolemia, familial, 1 Pathogenic:2
Likely pathogenic, criteria provided, single submitter | curation;literature only | Cardiovascular Research Group, Instituto Nacional de Saude Doutor Ricardo Jorge | Mar 01, 2016 | - - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Laboratory of molecular diagnosis of dyslipidemias, Università egli studi di Napoli Federico II | May 24, 2021 | - - |
Familial hypercholesterolemia Pathogenic:2
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Dec 11, 2023 | This sequence change replaces serine, which is neutral and polar, with phenylalanine, which is neutral and non-polar, at codon 580 of the LDLR protein (p.Ser580Phe). This variant is present in population databases (no rsID available, gnomAD 0.0009%). This missense change has been observed in individuals with clinical features of autosomal dominant and autosomal recessive familial hypercholesterolemia (PMID: 21865347, 31947532, 32977124; Invitae). ClinVar contains an entry for this variant (Variation ID: 438325). 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 with a positive predictive value of 95%. For these reasons, this variant has been classified as Pathogenic. - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Color Diagnostics, LLC DBA Color Health | Jun 07, 2022 | This missense variant (also known as p.Ser559Phe in the mature protein) replaces serine with phenylalanine at codon 580 in the LDLR type B repeat 5 in the EGF precursor homology domain of the LDLR protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). This variant has been reported in nine unrelated individuals affected with familial hypercholesterolemia (PMID: 21865347, 34297352, Schoen et al. 2014 doi:10.1016/j.jacl.2014.02.029). This variant has also been observed in the compound heterozygous state with other pathogenic LDLR variants (p.Gly549Asp, p.Gly592Glu) in two unrelated individuals affected with homozygous familial hypercholesterolemia (PMID: 21865347, 31947532). Reduced LDL uptake activities were observed in leukocytes from two of the affected carriers (PMID: 21865347, 35474963). This variant has been identified in 1/251488 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Likely Pathogenic. - |
Cardiovascular phenotype Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Ambry Genetics | Feb 02, 2022 | The p.S580F variant (also known as c.1739C>T), located in coding exon 12 of the LDLR gene, results from a C to T substitution at nucleotide position 1739. The serine at codon 580 is replaced by phenylalanine, an amino acid with highly dissimilar properties. This alteration is located immediately adjacent to the YWTD motif in the LDLR class B repeat 5. This variant has been previously reported in both the heterozygous and compound heterozygous states (with LDLR p.G549D and p.G592E mutations) in individuals reported to have a clinical diagnosis of familial hypercholesterolemia (Romano M et al. J. Lipid Res. 2011;52:2095-100; Di Taranto MD et al. J Clin Med. 2020 Jan;9(1); Di Taranto MD et al. Clin Genet. 2021 11;100(5):529-541). LDLR activity was reduced in lymphocytes derived from both heterozygous and a compound heterozygous individuals, with cells from the heterozygous patient exhibiting ~65% of the LDLR activity in control cells and cells from a compound heterozygote displaying 30-40% of control LDLR activity (Romano M et al. J. Lipid Res. 2011;52:2095-100). Internal structural analysis predicts that this variant results in a significant decrease in structural stability (Jeon H et al. Nat Struct Biol. 2001 Jun;8(6):499-504; Ambry internal data). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the majority of available evidence to date, this variant is likely to be pathogenic. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at