rs1057519658
Variant summary
Our verdict is Pathogenic. Variant got 13 ACMG points: 13P and 0B. PS1_ModeratePM1PM2PM5PP3_StrongPP5
The NM_000527.5(LDLR):c.672C>A(p.Asp224Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). 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. D224G) 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 13 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
LDLR | NM_000527.5 | c.672C>A | p.Asp224Glu | missense_variant | 4/18 | ENST00000558518.6 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
LDLR | ENST00000558518.6 | c.672C>A | p.Asp224Glu | missense_variant | 4/18 | 1 | NM_000527.5 | P3 |
Frequencies
GnomAD3 genomes ? Cov.: 33
GnomAD4 exome Data not reliable, filtered out with message: AC0;AS_VQSR AF: 0.00 AC: 0AN: 1408394Hom.: 0 Cov.: 34 AF XY: 0.00 AC XY: 0AN XY: 701546
GnomAD4 genome ? Cov.: 33
ClinVar
Submissions by phenotype
Hypercholesterolemia, familial, 1 Pathogenic:1Uncertain:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Molecular Genetics, Royal Melbourne Hospital | Mar 30, 2023 | This sequence change is predicted to replace aspartic acid with glutamic acid at codon 224 of the LDLR protein, p.(Asp224Glu). The aspartic acid residue is highly conserved (100 vertebrates, UCSC), and is located in the fifth low-density lipoprotein receptor class A domain. There is a small physicochemical difference between aspartic acid and glutamic acid. The variant is absent in a large population cohort (gnomAD v2.1), and has been identified in at least two probands with suspected familial hypercholesterolaemia (Royal Melbourne Hospital; ClinVar: SCV000503208.1). Multiple lines of computational evidence predict a deleterious effect for the missense substitution (7/7 algorithms). Many alternative missense changes at this position (p.Asp224Val, p.Asp224Gly, p.Asp224Ala, p.Asp224Asn) have been reported in familial hypercholesterolaemia cases (ClinVar), including the well-established pathogenic FH PORTUGAL variant (p.Asp224Asn; PMID: 1301956, 17765246). Based on the classification scheme RMH ACMG Guidelines v1.2.1, this variant is classified as LIKELY PATHOGENIC. Following criteria are met: PM2, PM5, PS4_Supporting, PP3. - |
Uncertain significance, criteria provided, single submitter | clinical testing | Centre de Génétique Moléculaire et Chromosomique, Unité de génétique de l'Obésité et des Dyslipidémies, APHP, GH Hôpitaux Universitaires Pitié-Salpêtrière / Charles-Foix | Dec 16, 2016 | subject mutated among 2600 FH index cases screened = 1 / other mutation at same codon / Software predictions: Conflicting - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at