rs10417394
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Variant summary
Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2BP4_ModerateBP6BP7
The NM_000527.5(LDLR):c.498C>T(p.Ala166=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000249 in 1,614,054 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).
Frequency
Genomes: 𝑓 0.0014 ( 0 hom., cov: 33)
Exomes 𝑓: 0.00013 ( 1 hom. )
Consequence
LDLR
NM_000527.5 synonymous
NM_000527.5 synonymous
Scores
2
Clinical Significance
Conservation
PhyloP100: -0.354
Genes affected
LDLR (HGNC:6547): (low density lipoprotein receptor) The low density lipoprotein receptor (LDLR) gene family consists of cell surface proteins involved in receptor-mediated endocytosis of specific ligands. The encoded protein is normally bound at the cell membrane, where it binds low density lipoprotein/cholesterol and is taken into the cell. Lysosomes release the cholesterol, which is made available for repression of microsomal enzyme 3-hydroxy-3-methylglutaryl coenzyme A (HMG CoA) reductase, the rate-limiting step in cholesterol synthesis. At the same time, a reciprocal stimulation of cholesterol ester synthesis takes place. Mutations in this gene cause the autosomal dominant disorder, familial hypercholesterolemia. Alternate splicing results in multiple transcript variants.[provided by RefSeq, May 2022]
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ACMG classification
Classification made for transcript
Verdict is Likely_benign. Variant got -2 ACMG points.
PM2
?
Very rare variant in population databases, with high coverage;
BP4
?
Computational evidence support a benign effect (BayesDel_noAF=-0.42).
BP6
?
Variant 19-11105404-C-T is Benign according to our data. Variant chr19-11105404-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 328050.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=1, Benign=3, Likely_benign=1}. Variant chr19-11105404-C-T is described in Lovd as [Benign].
BP7
?
Synonymous conserved (PhyloP=-0.354 with no splicing effect.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
LDLR | NM_000527.5 | c.498C>T | p.Ala166= | synonymous_variant | 4/18 | ENST00000558518.6 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
LDLR | ENST00000558518.6 | c.498C>T | p.Ala166= | synonymous_variant | 4/18 | 1 | NM_000527.5 | P3 |
Frequencies
GnomAD3 genomes ? AF: 0.00141 AC: 214AN: 152246Hom.: 0 Cov.: 33
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GnomAD3 exomes AF: 0.000358 AC: 90AN: 251292Hom.: 0 AF XY: 0.000294 AC XY: 40AN XY: 135880
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GnomAD4 exome AF: 0.000126 AC: 184AN: 1461690Hom.: 1 Cov.: 33 AF XY: 0.000110 AC XY: 80AN XY: 727156
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GnomAD4 genome ? AF: 0.00143 AC: 218AN: 152364Hom.: 0 Cov.: 33 AF XY: 0.00140 AC XY: 104AN XY: 74506
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ClinVar
Significance: Conflicting classifications of pathogenicity
Submissions summary: Uncertain:1Benign:6
Revision: criteria provided, conflicting classifications
LINK: link
Submissions by phenotype
Familial hypercholesterolemia Benign:3
Likely benign, no assertion criteria provided | clinical testing | Natera, Inc. | Oct 25, 2019 | - - |
Benign, criteria provided, single submitter | clinical testing | Invitae | Feb 01, 2024 | - - |
Benign, criteria provided, single submitter | clinical testing | Color Diagnostics, LLC DBA Color Health | Jul 17, 2017 | - - |
Hypercholesterolemia, familial, 1 Uncertain:1Benign:1
Benign, no assertion criteria provided | research | Laboratorium voor Moleculaire Diagnostiek Experimentele Vasculaire Geneeskunde, Academisch Medisch Centrum | - | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Jun 14, 2016 | - - |
not provided Benign:1
Benign, criteria provided, single submitter | clinical testing | Quest Diagnostics Nichols Institute San Juan Capistrano | Mar 07, 2023 | - - |
Cardiovascular phenotype Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Ambry Genetics | Dec 27, 2017 | This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. - |
Computational scores
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BayesDel_noAF
Benign
CADD
Benign
DANN
Benign
Splicing
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Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at