rs879254709
Variant summary
Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PM1PM2PP3_Strong
The NM_000527.5(LDLR):c.889A>C(p.Asn297His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000186 in 1,610,976 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 Uncertain significance (★★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. N297S) has been classified as Uncertain significance.
Frequency
Consequence
NM_000527.5 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_pathogenic. Variant got 8 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
LDLR | NM_000527.5 | c.889A>C | p.Asn297His | missense_variant | 6/18 | ENST00000558518.6 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
LDLR | ENST00000558518.6 | c.889A>C | p.Asn297His | missense_variant | 6/18 | 1 | NM_000527.5 | P3 |
Frequencies
GnomAD3 genomes ? AF: 0.0000132 AC: 2AN: 151940Hom.: 0 Cov.: 32
GnomAD4 exome AF: 6.85e-7 AC: 1AN: 1459036Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0AN XY: 725834
GnomAD4 genome ? AF: 0.0000132 AC: 2AN: 151940Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1AN XY: 74212
ClinVar
Submissions by phenotype
Hypercholesterolemia, familial, 1 Pathogenic:1Uncertain:3
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 | Feb 28, 2022 | The NM_000527.5(LDLR):c.889A>C (p.Asn297His) variant is classified as Uncertain significance - insufficient evidence for Familial Hypercholesterolemia by applying evidence codes PM2, PS4_supporting 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). The supporting evidence is as follows: PM2 - PopMax MAF = 1/24948 = 0.00004 (0.004%) in African/African-American 8692 exomes plus 16256 genomes (gnomAD v2.1.1), so PM2 is Met. PS4_supporting - Variant meets PM2 and is identified in at least 1 index case with DLCN>6 (definite heterozygous hypercholesterolemia) from The Netherlands (PMID: 16250003) and at least 1 index case with DLCN>6 from Spain (PMID: 19318025), so PS4_Supporting is Met. PP4 - Variant meets PM2 and is identified in at least 1 index case with DLCN>6 (definite heterozygous hypercholesterolemia) from The Netherlands (PMID: 16250003) and at least 1 index case with DLCN>6 from Spain (PMID: 19318025), so PP4 is Met. - |
Uncertain significance, criteria provided, single submitter | literature only | LDLR-LOVD, British Heart Foundation | Mar 25, 2016 | - - |
Uncertain significance, criteria provided, single submitter | research | Fundacion Hipercolesterolemia Familiar | Mar 01, 2016 | - - |
not provided Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Aug 05, 2022 | Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 19318025, 16250003) - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at