rs750474121
Variant summary
Our verdict is Uncertain significance. Variant got -4 ACMG points: 0P and 4B. BS3
This summary comes from the ClinGen Evidence Repository: The NM_000527.5(LDLR):c.292G>A (p.Gly98Ser) variant is classified as Uncertain significance - insufficient evidence for Familial Hypercholesterolemia by applying ACMG/AMP evidence code BS3 as defined by the ClinGen Familial Hypercholesterolemia Expert Panel LDLR-specific variant curation guidelines (specification version 1.2) on 23 February 2024. The supporting evidence is as follows:BS3: Level 1 assays (PMID 28645073 - Jiang et al., 2017) performed using heterologous cells (CHO-ldlA7) with Western blot, flow cytometry and confocal microscopy, showed normal expression (95%), binding (98%) and uptake (110%), consistent with no damaging effect. LINK:https://erepo.genome.network/evrepo/ui/classification/CA042749/MONDO:0007750/013
Frequency
Genomes: 𝑓 0.000026 ( 0 hom., cov: 31)
Exomes 𝑓: 0.000031 ( 0 hom. )
Consequence
LDLR
NM_000527.5 missense
NM_000527.5 missense
Scores
5
9
5
Clinical Significance
Conservation
PhyloP100: 4.20
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]
Genome browser will be placed here
ACMG classification
Classification made for transcript
Verdict is Uncertain_significance. Variant got -4 ACMG points.
BS3
For more information check the summary or visit ClinGen Evidence Repository.
Transcripts
RefSeq
| Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
|---|---|---|---|---|---|---|---|---|
| LDLR | NM_000527.5 | c.292G>A | p.Gly98Ser | missense_variant | 3/18 | ENST00000558518.6 | NP_000518.1 |
Ensembl
Frequencies
GnomAD3 genomes 0.0000263 AC: 4AN: 152168Hom.: 0 Cov.: 31
GnomAD3 genomes
AF:
AC:
4
AN:
152168
Hom.:
Cov.:
31
Gnomad AFR
AF:
Gnomad AMI
AF:
Gnomad AMR
AF:
Gnomad ASJ
AF:
Gnomad EAS
AF:
Gnomad SAS
AF:
Gnomad FIN
AF:
Gnomad MID
AF:
Gnomad NFE
AF:
Gnomad OTH
AF:
GnomAD3 exomes AF: 0.0000358 AC: 9AN: 251474Hom.: 0 AF XY: 0.0000294 AC XY: 4AN XY: 135916
GnomAD3 exomes
AF:
AC:
9
AN:
251474
Hom.:
AF XY:
AC XY:
4
AN XY:
135916
Gnomad AFR exome
AF:
Gnomad AMR exome
AF:
Gnomad ASJ exome
AF:
Gnomad EAS exome
AF:
Gnomad SAS exome
AF:
Gnomad FIN exome
AF:
Gnomad NFE exome
AF:
Gnomad OTH exome
AF:
GnomAD4 exome AF: 0.0000315 AC: 46AN: 1461466Hom.: 0 Cov.: 31 AF XY: 0.0000179 AC XY: 13AN XY: 727030
GnomAD4 exome
AF:
AC:
46
AN:
1461466
Hom.:
Cov.:
31
AF XY:
AC XY:
13
AN XY:
727030
Gnomad4 AFR exome
AF:
Gnomad4 AMR exome
AF:
Gnomad4 ASJ exome
AF:
Gnomad4 EAS exome
AF:
Gnomad4 SAS exome
AF:
Gnomad4 FIN exome
AF:
Gnomad4 NFE exome
AF:
Gnomad4 OTH exome
AF:
GnomAD4 genome 0.0000263 AC: 4AN: 152168Hom.: 0 Cov.: 31 AF XY: 0.0000269 AC XY: 2AN XY: 74340
GnomAD4 genome
AF:
AC:
4
AN:
152168
Hom.:
Cov.:
31
AF XY:
AC XY:
2
AN XY:
74340
Gnomad4 AFR
AF:
Gnomad4 AMR
AF:
Gnomad4 ASJ
AF:
Gnomad4 EAS
AF:
Gnomad4 SAS
AF:
Gnomad4 FIN
AF:
Gnomad4 NFE
AF:
Gnomad4 OTH
AF:
Alfa
AF:
Hom.:
Bravo
AF:
ExAC
AF:
AC:
7
Asia WGS
AF:
AC:
1
AN:
3478
ClinVar
Significance: Uncertain significance
Submissions summary: Pathogenic:2Uncertain:10
Revision: reviewed by expert panel
LINK: link
Submissions by phenotype
Hypercholesterolemia, familial, 1 Pathogenic:2Uncertain:4
| 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 23, 2024 | The NM_000527.5(LDLR):c.292G>A (p.Gly98Ser) variant is classified as Uncertain significance - insufficient evidence for Familial Hypercholesterolemia by applying ACMG/AMP evidence code BS3 as defined by the ClinGen Familial Hypercholesterolemia Expert Panel LDLR-specific variant curation guidelines (specification version 1.2) on 23 February 2024. The supporting evidence is as follows: BS3: Level 1 assays (PMID 28645073 - Jiang et al., 2017) performed using heterologous cells (CHO-ldlA7) with Western blot, flow cytometry and confocal microscopy, showed normal expression (95%), binding (98%) and uptake (110%), consistent with no damaging effect. - |
| Likely pathogenic, criteria provided, single submitter | literature only | LDLR-LOVD, British Heart Foundation | Mar 25, 2016 | - - |
| Uncertain significance, criteria provided, single submitter | clinical testing | First Hospital of Lanzhou University, Lanzhou University | Feb 23, 2024 | A 38-year-old female proband carried a compliant heterozygous variant (c.292G>A,c.1864G> A and c.1448G> A, according to the ACMG guidelines they were separately classified as Uncertain significance, Likely pathogenic and pathogenic).The proband presented with a xanthoma, corneal aneurysm, and coronary artery diseaseThe patient's serum cholesterol concentration remained greater than 13 mmol/L after receiving intensive statin, Evolocumab and Inclisiran therapy.We speculate that the hepatocytes of the proband indicate the almostly absence of LDLR. The proband's mother, sister, and son all carried the c.292G>A,c.1864G> A variant. The proband father, both brothers and daughter carried the c.1448G> A variant. Without exception, all of her relatives showed hypercholesterolemia, but no atherosclerosis, xanthoma, or corneal aneurysm in the other relatives except the proband. Pedigree co-segregation evidence suggests that the three variants may be pathogenic variants in this familial hypercholesterolemic family. - |
| Uncertain significance, criteria provided, single submitter | clinical testing | Victorian Clinical Genetics Services, Murdoch Childrens Research Institute | Jul 16, 2023 | Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as VUS-3C. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with familial hypercholesterolaemia 1 (FH; MIM#143890). (I) 0108 - This gene is associated with both recessive and dominant disease. Variants have been reported in heterozygous, compound heterozygous and homozygous states with the recessive disease being more severe (OMIM, PMID: 10978268). (I) 0112 - The condition associated with this gene has incomplete penetrance (PMID: 24404629). (I) 0200 - Variant is predicted to result in a missense amino acid change from glycine to serine. (I) 0251 - This variant is heterozygous. (I) 0304 - Variant is present in gnomAD (v2) <0.01 (10 heterozygotes, 0 homozygotes). (SP) 0502 - Missense variant with pathogenic in silico predictions and low conservation with a minor Grantham change. (I) 0600 - Variant is located in the annotated Ldl_recept_a domain (DECIPHER). (I) 0710 - Another missense variant comparable to the one identified in this case has inconclusive previous evidence for pathogenicity. This alternative change, p.(Gly98Ala), has been reported as a VUS (ClinVar). Additional alternative changes with higher Grantham scores, p.(Gly98Cys) and p.(Gly98Arg), have also been reported, however these are not deemed comparable. (I) 0808 - Previous reports of pathogenicity for this variant are conflicting. This variant has been reported as a VUS in a clinical testing setting (ClinVar, LOVD), but also as pathogenic in three individuals with atherosclerotic cardiovascular disease, premature myocardial infarction, and/or FH (PMID: 30971288, PMID: 16250003, PMID: 30333156). It has also been observed in two individuals with FH, who had an additional causative variant in the LDLR or APOB gene (PMID: 28645073, PMID: 27919364). Lastly, it has been observed in at least three individuals as a secondary finding (PMID: 35727495, PMID: 31130284). (I) 0905 - No published segregation evidence has been identified for this variant. (I) 1004 - This variant has moderate functional evidence supporting normal protein function. Functional studies using transfected CHO cells have proven this variant does not affect protein expression, activity and binding (PMID: 28645073). (SB) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign - |
| Uncertain significance, criteria provided, single submitter | clinical testing | All of Us Research Program, National Institutes of Health | May 10, 2024 | This missense variant (also known as p.Gly77Ser in the mature protein) replaces glycine with serine at codon 98 of the LDLR protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). A functional study has shown that this variant does not impact LDLR binding, uptake, or localization (PMID: 28645073). This variant has been reported in individuals affected with familial hypercholesterolemia (PMID: 16250003, 28645073, 34456200, 34573395; Zhu et al 2017 DOI: 10.1016/j.ijcme.2017.01.004) and in an individual affected with premature myocardial infarction (PMID: 30637778). This variant has been identified in 10/282872 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. - |
not provided Uncertain:3
| Uncertain significance, criteria provided, single submitter | clinical testing | Quest Diagnostics Nichols Institute San Juan Capistrano | Oct 26, 2023 | The LDLR c.292G>A (p.Gly98Ser) variant has been reported in the published literature in affected individuals with familial hypercholesterolemia (PMIDs: 16250003 (2005), 27919364 (2017), 30526649 (2018), 30637778 (2019), and 34456200 (2021)). A functional study found this variant is not damaging to LDLR binding, uptake, or localization, however, when combined with other variants a damaging impact has been noted (PMID: 28645073 (2017)). The frequency of this variant in the general population, 0.00025 (5/19954 chromosomes (Genome Aggregation Database, http://gnomad.broadinstitute.org)), is uninformative in the assessment of its pathogenicity. Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded predictions that this variant is damaging. Based on the available information, we are unable to determine the clinical significance of this variant. - |
| Uncertain significance, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Feb 22, 2021 | The p.Gly98Ser variant in LDLR (also reported as p.Gly77Ser) has been reported in at least 1 heterozygous Dutch individual with hypercholesterolemia (Fouchier 2005), and in 2 Chinese individuals with severe hypercholesterolemia, both of whom also carried p.Asp622Asn in cis with this variant and one of whom harbored a third LDLR variant that was in trans with the other two variants (Jiang 2017, Zhu 2017). This variant has been identified in 4/18870 East Asian chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org/; dbSNP rs750474121) and is reported in ClinVar (Variation ID: 251118). Please note that for diseases with clinical variability, reduced penetrance, or recessive inheritance, pathogenic variants may be present at a low frequency in the general population. In vitro functional studies suggest that the p.Gly98Ser variant, when present in isolation, may not significantly impact protein function (Jiang 2017), but may affect LDL binding when present in cis with the p.Asp622Asn variant (Jiang 2017). Computational prediction tools and conservation analysis do not provide strong support for or against an impact to the protein. In summary, the clinical significance of the p.Gly98Ser variant is uncertain. ACMG/AMP criteria applied: None. - |
| Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Jun 18, 2019 | In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; This variant is associated with the following publications: (PMID: 32041611, 30971288, 28645073, 16250003, 27919364, 30637778, 30526649, 30333156) - |
Familial hypercholesterolemia Uncertain:2
| Uncertain significance, no assertion criteria provided | clinical testing | Natera, Inc. | Feb 21, 2020 | - - |
| Uncertain significance, criteria provided, single submitter | clinical testing | Color Diagnostics, LLC DBA Color Health | Feb 01, 2023 | This missense variant (also known as p.Gly77Ser in the mature protein) replaces glycine with serine at codon 98 of the LDLR protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). A functional study has shown that this variant does not impact LDLR binding, uptake, or localization (PMID: 28645073). This variant has been reported in individuals affected with familial hypercholesterolemia (PMID: 16250003, 28645073, 34456200, 34573395; Zhu et al 2017 DOI: 10.1016/j.ijcme.2017.01.004) and in an individual affected with premature myocardial infarction (PMID: 30637778). This variant has been identified in 10/282872 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. - |
not specified Uncertain:1
| Uncertain significance, criteria provided, single submitter | clinical testing | Mendelics | May 04, 2022 | - - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
BayesDel_addAF
Uncertain
D
BayesDel_noAF
Pathogenic
CADD
Benign
DANN
Uncertain
DEOGEN2
Pathogenic
D;.;.;.;.
Eigen
Benign
Eigen_PC
Benign
FATHMM_MKL
Uncertain
D
LIST_S2
Uncertain
D;D;D;D;D
M_CAP
Pathogenic
D
MetaRNN
Uncertain
D;D;D;D;D
MetaSVM
Pathogenic
D
MutationAssessor
Uncertain
M;.;M;M;M
PrimateAI
Benign
T
PROVEAN
Uncertain
D;D;N;D;D
REVEL
Pathogenic
Sift
Uncertain
D;D;T;D;D
Sift4G
Uncertain
D;D;T;D;D
Polyphen
D;.;.;.;.
Vest4
MutPred
Gain of phosphorylation at G98 (P = 0.0576);Gain of phosphorylation at G98 (P = 0.0576);Gain of phosphorylation at G98 (P = 0.0576);Gain of phosphorylation at G98 (P = 0.0576);Gain of phosphorylation at G98 (P = 0.0576);
MVP
MPC
ClinPred
D
GERP RS
RBP_binding_hub_radar
RBP_regulation_power_radar
Varity_R
gMVP
Splicing
Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at