rs374045590
Variant summary
Our verdict is Pathogenic. Variant got 26 ACMG points: 26P and 0B. PS1_Very_StrongPM1PM2PM5PP3_StrongPP5_Very_Strong
The NM_000527.5(LDLR):c.2475C>A(p.Asn825Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000274 in 1,461,822 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 Pathogenic (★★★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely pathogenicin ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. N825D) has been classified as Likely pathogenic.
Frequency
Consequence
NM_000527.5 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 26 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
LDLR | NM_000527.5 | c.2475C>A | p.Asn825Lys | missense_variant | 17/18 | ENST00000558518.6 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
LDLR | ENST00000558518.6 | c.2475C>A | p.Asn825Lys | missense_variant | 17/18 | 1 | NM_000527.5 | P3 |
Frequencies
GnomAD3 genomes ? Cov.: 31
GnomAD3 exomes AF: 0.00000398 AC: 1AN: 251458Hom.: 0 AF XY: 0.00000736 AC XY: 1AN XY: 135912
GnomAD4 exome AF: 0.00000274 AC: 4AN: 1461822Hom.: 0 Cov.: 32 AF XY: 0.00000413 AC XY: 3AN XY: 727208
GnomAD4 genome ? Cov.: 31
ClinVar
Submissions by phenotype
Hypercholesterolemia, familial, 1 Pathogenic:5
Pathogenic, no assertion criteria provided | research | Laboratorium voor Moleculaire Diagnostiek Experimentele Vasculaire Geneeskunde, Academisch Medisch Centrum | - | - - |
Pathogenic, reviewed by expert panel | curation | ClinGen Familial Hypercholesterolemia Variant Curation Expert Panel | Mar 20, 2023 | The NM_000527.5 (LDLR):c.2475C>A (p.Asn825Lys) variant is classified as Pathogenic for Familial Hypercholesterolemia by applying evidence codes (PM2, PP3, PS3, PP4, PS4, PP1_Strong) 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: PopMax MAF= 0.00001 in European (Non-Finnish) population (gnomAD v2.1.1). PP3: REVEL = 0.802. PS3: Level 1 experiment using heterologous cells (CHO), the experiments shown 50-60% LDL uptake, and normal LDL-LDLR binding (95%) and normal cell surface LDLR (95%), Etxebarria et al, 2015, Unidad de Biofísica (CSIC, UPV/EHU), Departamento de Bioquímica, Universidad del País Vasco, Spain, PMID25378237. PP4: Variant meets PM2 and is identified in >1 index cases who fulfil FH diagnostic criteria after alternative causes of high cholesterol were excluded. PS4: Variant meets PM2 and is identified in 22 unrelated index cases who fulfil FH diagnostic criteria. Four index cases from Centre de Génétique Moléculaire et Chromosomique, Unité de génétique de l'Obésité et des Dyslipidémies (APHP.Sorbonne Université, Hôpital de la Pitié-Salpêtrière), three of them had DLCN score >=6, one met Simon Broome possible for FH. Three index cases with DLCN score >=6, from Robarts Research Institute, Canada. One case fulfil criteria of TC and LDLc higher than the 95th percentile, with presence of tendon xanthomata, CAD in the proband or in a first degree relative, Chaves et al, 2001, Institute of cytological research and service of endocrinology and nutrition, University of Valencia, Spain, PMID 11600564. Fourteen index cases fulfil 2 of 3 criteria of: 1) TC>8mmol/l, LDL>6mmol/l, TG<2.5mmol/l, 2) CAD before 60yr or family history of CAD, 3) presence of tendon xanthoma, Brusgaard et al, 2006, Department of clinical biochemistry and clinical genetics, Odense University hospital, Denmark, PMID 16542394. PP1_Strong: Variant segregates with FH phenotype in 16 informative meiosis from more than 3 families. Two affected relatives, one each from 2 families tested positive for the variant from Robarts Research Institute, Canada. Fourteen affected relatives from unknown number of families tested positive for the variant, Brusgaard et al, 2006, Department of clinical biochemistry and clinical genetics, Odense University hospital, Denmark, PMID 16542394. PS1 not met: One other missense variant that leads to the same amino acid change at same codon, NM_000527.5 (LDLR):c.2475C>G (p.Asn825Lys), (ClinVarID 161265), is classified as Likely Pathogenic by these guidelines, therefore PS1 is not met. PM5 not met: One other missense variants in the same codon: NM_000527.5 (LDLR):c.2473A>G (p.Asn825Asp), (ClinVarID 252340) is classified as Likely Pathogenic by these guidelines, therefore PM5 not met. - |
Likely pathogenic, criteria provided, single submitter | literature only | LDLR-LOVD, British Heart Foundation | Mar 25, 2016 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | U4M - Lille University & CHRU Lille, Université de Lille - CHRU de Lille | Mar 30, 2017 | - - |
Likely pathogenic, criteria provided, single submitter | research | Fundacion Hipercolesterolemia Familiar | Mar 01, 2016 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at