chr19-11102706-G-A
Variant summary
Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PM2PP3PP4PS4_Supporting
This summary comes from the ClinGen Evidence Repository: The NM_000527.5(LDLR):c.233G>A (p.Arg78His) variant is classified as Uncertain significance - insufficient evidence for Familial Hypercholesterolemia by applying evidence codes PM2, PP3, 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 = 0.0001202 (0.012%) in African/African American exomes+genomes (gnomAD v2.1.1). It is below 0.02%, so PM2 is met.PP3 - REVEL = 0.806. It is above 0.75, so PP3 is met.PS4_supporting - variant meets PM2 and was identified in:- 1 index case with SB criteria of FH from PMID 31993549 (Garg et al., 2019), North America;- 1 index case with DLCN at least 8 (TC>10mmol/L and xanthomas) from PMID 27830735 (Jiang et al. 2016), China;- 1 index case with MEDPED criteria of FH from Benyahya et al. (2010) (paper cited in HGMD), Morocco;3 unrelated index cases, so PS4_Supporting is met.PP4 - variant meets PM2 and was identified in 3 unrelated index cases who fulfill clinical criteria for FH after alternative causes of high cholesterol were excluded (please see PS4 for details), so PP4 is met. LINK:https://erepo.genome.network/evrepo/ui/classification/CA042534/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 5 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
LDLR | NM_000527.5 | c.233G>A | p.Arg78His | missense_variant | 3/18 | ENST00000558518.6 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
LDLR | ENST00000558518.6 | c.233G>A | p.Arg78His | missense_variant | 3/18 | 1 | NM_000527.5 | P3 |
Frequencies
GnomAD3 genomes AF: 0.0000526 AC: 8AN: 152192Hom.: 0 Cov.: 31
GnomAD3 exomes AF: 0.0000557 AC: 14AN: 251490Hom.: 0 AF XY: 0.0000809 AC XY: 11AN XY: 135920
GnomAD4 exome AF: 0.0000862 AC: 126AN: 1461474Hom.: 0 Cov.: 31 AF XY: 0.0000922 AC XY: 67AN XY: 727044
GnomAD4 genome AF: 0.0000526 AC: 8AN: 152192Hom.: 0 Cov.: 31 AF XY: 0.0000269 AC XY: 2AN XY: 74352
ClinVar
Submissions by phenotype
Hypercholesterolemia, familial, 1 Pathogenic:1Uncertain:4Benign:1
Uncertain significance, reviewed by expert panel | curation | ClinGen Familial Hypercholesterolemia Variant Curation Expert Panel | Aug 28, 2022 | The NM_000527.5(LDLR):c.233G>A (p.Arg78His) variant is classified as Uncertain significance - insufficient evidence for Familial Hypercholesterolemia by applying evidence codes PM2, PP3, 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 = 0.0001202 (0.012%) in African/African American exomes+genomes (gnomAD v2.1.1). It is below 0.02%, so PM2 is met. PP3 - REVEL = 0.806. It is above 0.75, so PP3 is met. PS4_supporting - variant meets PM2 and was identified in: - 1 index case with SB criteria of FH from PMID 31993549 (Garg et al., 2019), North America; - 1 index case with DLCN at least 8 (TC>10mmol/L and xanthomas) from PMID 27830735 (Jiang et al. 2016), China; - 1 index case with MEDPED criteria of FH from Benyahya et al. (2010) (paper cited in HGMD), Morocco; 3 unrelated index cases, so PS4_Supporting is met. PP4 - variant meets PM2 and was identified in 3 unrelated index cases who fulfill clinical criteria for FH after alternative causes of high cholesterol were excluded (please see PS4 for details), so PP4 is met. - |
Likely benign, 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 / patient compound heterozygous (LDLC max 400mg/dL) / Software predictions: Damaging - |
Uncertain significance, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Apr 27, 2017 | This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. - |
Likely pathogenic, criteria provided, single submitter | literature only | LDLR-LOVD, British Heart Foundation | Mar 25, 2016 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | All of Us Research Program, National Institutes of Health | Nov 30, 2023 | This missense variant (also known as p.Arg57His in the mature protein) replaces arginine with histidine at codon 78 of the LDLR protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). To our knowledge, functional studies have not been performed for this variant. This variant has been reported in 3 individuals affected with hypercholesterolemia (PMID 20809525; Benyahya et al., 2010, 31993549). This variant has also been reported in 11 UK Biobank participants who had normal or modestly elevated LDL-C levels (doi: 10.1101/2021.08.12.21261563). This variant has been identified in 15/282884 chromosomes in the general population by the Genome Aggregation Database (gnomAD). 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. - |
Uncertain significance, criteria provided, single submitter | clinical testing | Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center | Mar 26, 2024 | - - |
not specified Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Oct 12, 2023 | Variant summary: LDLR c.233G>A (p.Arg78His) results in a non-conservative amino acid change in the encoded protein sequence. Three of four in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 5.6e-05 in 251490 control chromosomes (gnomAD). This frequency is not significantly higher than estimated for a pathogenic variant in LDLR causing Familial Hypercholesterolemia (5.6e-05 vs 0.0013), allowing no conclusion about variant significance. c.233G>A has been reported in the literature in individuals from Myocardial infarction and Hypercholesterolemia cohort studies, however, case specific information (co-occurrences/co-segregation) was not available to evaluate causality (examples: Trinder_2022, Do_2015 and Marduel_2010). These report(s) do not provide unequivocal conclusions about association of the variant with Familial Hypercholesterolemia. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 25487149, 31993549, 20809525, 34906840). Four submitters (including ClinGen Familial Hypercholesterolemia Variant Curation Expert Panel) have cited clinical-significance assessments for this variant to ClinVar after 2014 and classified the variant as VUS (n=3) and likely benign (n=1). Based on the evidence outlined above, the variant was classified as uncertain significance. - |
Familial hypercholesterolemia Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Color Diagnostics, LLC DBA Color Health | Dec 06, 2022 | This missense variant (also known as p.Arg57His in the mature protein) replaces arginine with histidine at codon 78 of the LDLR protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). To our knowledge, functional studies have not been performed for this variant. This variant has been reported in 3 individuals affected with hypercholesterolemia (PMID 20809525; Benyahya et al., 2010, 31993549). This variant has also been reported in 11 UK Biobank participants who had normal or modestly elevated LDL-C levels (doi: 10.1101/2021.08.12.21261563). This variant has been identified in 15/282884 chromosomes in the general population by the Genome Aggregation Database (gnomAD). 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