rs875989914
Variant summary
Our verdict is Uncertain significance. Variant got -2 ACMG points: 3P and 5B. BP4BS3PM2PP4
This summary comes from the ClinGen Evidence Repository: NM_000527.5(LDLR):c.1049G>A (p.Arg350Gln) variant is classified as Uncertain significance - conflicting evidence, for Familial Hypercholesterolemia by applying evidence codes PM2, BP4, BS3 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 = 0.0001157 (0.01%) in Latino/Admixed Americans exomes+genomes (gnomAD v2.1.1).. BP4: REVEL = 0.373. it is below 0.50, so splicing evaluation is required.Functional data on splicing not available.A) Variant not on limits.B) Variant does not create GT.Variant is predicted not to alter splicing.. BS3: Level 1 assays: PMID 31106925Heterologous cells (CHO), FACS assays - result - 100% LDLR expression, binding, and uptake. PP4: Variant meets PM2 and is identified in at least 1 index case with DLCN>=6/ from PMID 31106925, after alternative causes of high cholesterol were excluded. LINK:https://erepo.genome.network/evrepo/ui/classification/CA305299648/MONDO:0007750/013
Frequency
Consequence
NM_000527.5 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Uncertain_significance. Variant got -2 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
LDLR | NM_000527.5 | c.1049G>A | p.Arg350Gln | missense_variant | 7/18 | ENST00000558518.6 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
LDLR | ENST00000558518.6 | c.1049G>A | p.Arg350Gln | missense_variant | 7/18 | 1 | NM_000527.5 | P3 |
Frequencies
GnomAD3 genomes ? AF: 0.00000657 AC: 1AN: 152190Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.0000160 AC: 4AN: 250736Hom.: 0 AF XY: 0.00 AC XY: 0AN XY: 135626
GnomAD4 exome AF: 0.00000684 AC: 10AN: 1461052Hom.: 0 Cov.: 31 AF XY: 0.00000688 AC XY: 5AN XY: 726844
GnomAD4 genome ? AF: 0.00000657 AC: 1AN: 152190Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0AN XY: 74346
ClinVar
Submissions by phenotype
Hypercholesterolemia, familial, 1 Pathogenic:1Uncertain:2
Pathogenic, no assertion criteria provided | clinical testing | Department of Genetics of Metabolic Diseases, Institute of Medical & Molecular Genetics, Hospital Universitario Hospital La Paz | Jan 01, 2019 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | All of Us Research Program, National Institutes of Health | Dec 07, 2023 | - - |
Uncertain significance, reviewed by expert panel | curation | ClinGen Familial Hypercholesterolemia Variant Curation Expert Panel | Apr 28, 2023 | NM_000527.5(LDLR):c.1049G>A (p.Arg350Gln) variant is classified as Uncertain significance - conflicting evidence, for Familial Hypercholesterolemia by applying evidence codes PM2, BP4, BS3 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 = 0.0001157 (0.01%) in Latino/Admixed Americans exomes+genomes (gnomAD v2.1.1). . BP4: REVEL = 0.373. it is below 0.50, so splicing evaluation is required. Functional data on splicing not available. A) Variant not on limits. B) Variant does not create GT. Variant is predicted not to alter splicing. . BS3: Level 1 assays: PMID 31106925 Heterologous cells (CHO), FACS assays - result - 100% LDLR expression, binding, and uptake . PP4: Variant meets PM2 and is identified in at least 1 index case with DLCN>=6/ from PMID 31106925, after alternative causes of high cholesterol were excluded. - |
Familial hypercholesterolemia Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Color Diagnostics, LLC DBA Color Health | Apr 10, 2023 | This missense variant (also known as p.Arg329Gln in the mature protein) replaces arginine with glutamine at codon 350 of the LDLR protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). A functional study using transfected CHO cells has shown that this variant does not inhibit LDLR expression and LDL uptake (PMID: 31106925). This variant has been reported in an individual affected with familial hypercholesterolemia (PMID: 31106925). This variant has been identified in 4/250736 chromosomes in the general population by the Genome Aggregation Database (gnomAD). A different variant affecting the same codon, p.Arg350Pro, is considered to be disease-causing (ClinVar variation ID: 226343), suggesting that arginine at this position is important for LDLR protein function. The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at