rs745343524
Variant summary
Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2PP4PM5PS4_Supporting
This summary comes from the ClinGen Evidence Repository: The NM_000527.5(LDLR):c.1301C>A (p.Thr434Lys) variant is classified as Likely Pathogenic for Familial Hypercholesterolemia by applying evidence codes PS4_Supporting, PM2, PM5, 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). PS4_Supporting: Variant meets PM2 and is identified in 2 unrelated cases, as follows: 1 case with DLCN >=6 from Service de Biochimie et de Biologie Moléculaire, Hospices Civils de Lyon, Lyon, France; 1 case with clinical criteria based on Defesche J. 2000. Familial hypercholesterolemia. In: Betteridge J (ed): Lipids and Vascular Disease from PMID 11810272. So PS4_Supporting is met.PM2: PopMax MAF = 0.00001 (0.001%) in European (Non-Finnish) exomes+genomes (gnomAD v2.1.1). So, PM2 is met. PM5: 3 other missense variants in the same codon:- NM_000527.5(LDLR):c.1301C>G (p.Thr434Arg) (ClinVar ID 251774) - Pathogenic by these guidelines- NM_000527.5(LDLR):c.1301C>T (p.Thr434Met)(ClinVar ID 251775) - Unknown significance by these guidelines- NM_000527.5(LDLR):c.1300A>C (p.Thr434Pro)(ClinVar ID 496018) - Unknown significance by these guidelinesThere is 1 variant in the same codon classified as Pathogenic by these guidelines. PP4: Variant meets PM2. Identified in 1 FH case from Service de Biochimie et de Biologie Moléculaire, Hospices Civils de Lyon with clinical DLCN Criteria score ≥ 6, after alternative causes of high cholesterol were excluded. LINK:https://erepo.genome.network/evrepo/ui/classification/CA10585392/MONDO:0007750/013
Frequency
Consequence
NM_000527.5 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_pathogenic. Variant got 6 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
LDLR | NM_000527.5 | c.1301C>A | p.Thr434Lys | missense_variant | 9/18 | ENST00000558518.6 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
LDLR | ENST00000558518.6 | c.1301C>A | p.Thr434Lys | missense_variant | 9/18 | 1 | NM_000527.5 | P3 |
Frequencies
GnomAD3 genomes Cov.: 29
GnomAD3 exomes AF: 0.00000398 AC: 1AN: 251262Hom.: 0 AF XY: 0.00 AC XY: 0AN XY: 135874
GnomAD4 exome AF: 6.84e-7 AC: 1AN: 1461688Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0AN XY: 727146
GnomAD4 genome Cov.: 29
ClinVar
Submissions by phenotype
Hypercholesterolemia, familial, 1 Pathogenic:3Benign:1
Likely pathogenic, reviewed by expert panel | curation | ClinGen Familial Hypercholesterolemia Variant Curation Expert Panel | Oct 28, 2022 | The NM_000527.5(LDLR):c.1301C>A (p.Thr434Lys) variant is classified as Likely Pathogenic for Familial Hypercholesterolemia by applying evidence codes PS4_Supporting, PM2, PM5, 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). PS4_Supporting: Variant meets PM2 and is identified in 2 unrelated cases, as follows: 1 case with DLCN >=6 from Service de Biochimie et de Biologie Moléculaire, Hospices Civils de Lyon, Lyon, France; 1 case with clinical criteria based on Defesche J. 2000. Familial hypercholesterolemia. In: Betteridge J (ed): Lipids and Vascular Disease from PMID 11810272. So PS4_Supporting is met. PM2: PopMax MAF = 0.00001 (0.001%) in European (Non-Finnish) exomes+genomes (gnomAD v2.1.1). So, PM2 is met. PM5: 3 other missense variants in the same codon: - NM_000527.5(LDLR):c.1301C>G (p.Thr434Arg) (ClinVar ID 251774) - Pathogenic by these guidelines - NM_000527.5(LDLR):c.1301C>T (p.Thr434Met)(ClinVar ID 251775) - Unknown significance by these guidelines - NM_000527.5(LDLR):c.1300A>C (p.Thr434Pro)(ClinVar ID 496018) - Unknown significance by these guidelines There is 1 variant in the same codon classified as Pathogenic by these guidelines. PP4: Variant meets PM2. Identified in 1 FH case from Service de Biochimie et de Biologie Moléculaire, Hospices Civils de Lyon with clinical DLCN Criteria score ≥ 6, after alternative causes of high cholesterol were excluded. - |
Pathogenic, no assertion criteria provided | research | Laboratorium voor Moleculaire Diagnostiek Experimentele Vasculaire Geneeskunde, Academisch Medisch Centrum | - | - - |
Likely benign, 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 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at