rs373848925

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 1P and 0B. PP3

This summary comes from the ClinGen Evidence Repository: The NM_000527.5(LDLR):c.1516G>A (p.Val506Met) variant is classified as Uncertain significance - insufficient evidence for Familial Hypercholesterolemia by applying ACMG/AMP evidence code PP3 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: PP3: REVEL=0.757. LINK:https://erepo.genome.network/evrepo/ui/classification/CA034649/MONDO:0007750/013

Frequency

Genomes: 𝑓 0.000099 ( 0 hom., cov: 32)
Exomes 𝑓: 0.000021 ( 0 hom. )

Consequence

LDLR
ENST00000558518.6 missense

Scores

1
3
15

Clinical Significance

Uncertain significance reviewed by expert panel P:1U:6B:2

Conservation

PhyloP100: -0.553
Variant links:
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 1 ACMG points.

PP3
For more information check the summary or visit ClinGen Evidence Repository.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
LDLRNM_000527.5 linkuse as main transcriptc.1516G>A p.Val506Met missense_variant 10/18 ENST00000558518.6 NP_000518.1

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
LDLRENST00000558518.6 linkuse as main transcriptc.1516G>A p.Val506Met missense_variant 10/181 NM_000527.5 ENSP00000454071 P3P01130-1

Frequencies

GnomAD3 genomes
AF:
0.0000986
AC:
15
AN:
152190
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.0000724
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.000524
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.000385
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.0000294
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.0000636
AC:
16
AN:
251450
Hom.:
0
AF XY:
0.0000809
AC XY:
11
AN XY:
135908
show subpopulations
Gnomad AFR exome
AF:
0.0000615
Gnomad AMR exome
AF:
0.0000289
Gnomad ASJ exome
AF:
0.0000992
Gnomad EAS exome
AF:
0.000707
Gnomad SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.00
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.0000205
AC:
30
AN:
1461872
Hom.:
0
Cov.:
35
AF XY:
0.0000206
AC XY:
15
AN XY:
727246
show subpopulations
Gnomad4 AFR exome
AF:
0.0000299
Gnomad4 AMR exome
AF:
0.0000224
Gnomad4 ASJ exome
AF:
0.0000383
Gnomad4 EAS exome
AF:
0.000403
Gnomad4 SAS exome
AF:
0.0000116
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.00000719
Gnomad4 OTH exome
AF:
0.0000331
GnomAD4 genome
AF:
0.0000986
AC:
15
AN:
152190
Hom.:
0
Cov.:
32
AF XY:
0.000121
AC XY:
9
AN XY:
74348
show subpopulations
Gnomad4 AFR
AF:
0.0000724
Gnomad4 AMR
AF:
0.000524
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.000385
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.0000294
Gnomad4 OTH
AF:
0.00
Alfa
AF:
0.0000644
Hom.:
0
Bravo
AF:
0.000102
ESP6500AA
AF:
0.00
AC:
0
ESP6500EA
AF:
0.000116
AC:
1
ExAC
AF:
0.0000824
AC:
10
Asia WGS
AF:
0.000289
AC:
1
AN:
3478

ClinVar

Significance: Uncertain significance
Submissions summary: Pathogenic:1Uncertain:6Benign:2
Revision: reviewed by expert panel
LINK: link

Submissions by phenotype

Hypercholesterolemia, familial, 1 Pathogenic:1Uncertain:2Benign:1
Pathogenic, no assertion criteria providedresearchLaboratorium voor Moleculaire Diagnostiek Experimentele Vasculaire Geneeskunde, Academisch Medisch Centrum-- -
Likely benign, criteria provided, single submitterliterature onlyLDLR-LOVD, British Heart FoundationMar 25, 2016- -
Uncertain significance, criteria provided, single submitterclinical testingAll of Us Research Program, National Institutes of HealthSep 27, 2024This missense variant replaces valine with methionine at codon 506 of the LDLR protein. This variant is also known as p.Val485Met in the mature protein. This variant alters a conserved valine residue in the LDLR type B repeat 3 of the LDLR protein (a.a. 486-528), where pathogenic missense variants are found enriched (ClinVar-LDLR). Computational prediction tools indicate that this variant has a deleterious impact on protein structure and function. To our knowledge, functional studies have not been performed for this variant. This variant has been reported in individuals affected with familial hypercholesterolemia (PMID: 20145306, 32770674, 33740630). One of these individuals also carried a large duplication variant encompassing LDLR exons 3-12 (PMID: 20145306). This variant has also been reported in an individual affected with early-onset myocardial infarction (PMID: 25487149). This variant has been identified in 16/251450 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The elevated variant allele frequency in the general population indicates that this variant may not be disease-causing. However, additional studies are necessary to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. -
Uncertain significance, reviewed by expert panelcurationClinGen Familial Hypercholesterolemia Variant Curation Expert PanelFeb 23, 2024The NM_000527.5(LDLR):c.1516G>A (p.Val506Met) variant is classified as Uncertain significance - insufficient evidence for Familial Hypercholesterolemia by applying ACMG/AMP evidence code PP3 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: PP3: REVEL=0.757. -
Familial hypercholesterolemia Uncertain:1Benign:1
Likely benign, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpJan 04, 2024- -
Uncertain significance, criteria provided, single submitterclinical testingColor Diagnostics, LLC DBA Color HealthApr 24, 2023This missense variant (also known as p.Val485Met in the mature protein) replaces valine with methionine at codon 506 of the LDLR protein. Computational prediction suggests that this variant may have a 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 an individual affected with familial hypercholesterolemia, who also carried a large duplication variant encompassing LDLR exons 3-12 (PMID: 20145306). This variant has also been reported in another individual affected with familial hypercholesterolemia (PMID: 32770674) and in an individual affected with early-onset myocardial infarction (PMID: 25487149). This variant has been identified in 16/251450 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The elevated variant allele frequency in the general population indicates that this variant may not be disease-causing. However, additional studies are necessary 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 submitterclinical testingWomen's Health and Genetics/Laboratory Corporation of America, LabCorpAug 12, 2024Variant summary: LDLR c.1516G>A (p.Val506Met) results in a conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 6.4e-05 in 251450 control chromosomes. This frequency is not significantly higher than estimated for a pathogenic variant in LDLR causing Familial Hypercholesterolemia (6.4e-05 vs 0.0013), allowing no conclusion about variant significance. c.1516G>A has been reported in the literature in several individuals affected with Familial Hypercholesterolemia, including one who had a second LDLR variant, and it has been reported in one individual from an early myocardial infarction cohort (e.g. Chmara_2010, Do_2015, Rieck_2020, Leren_2021, Noto_2022); however these cases lacked strong evidence for causality (i.e. segregation data). Therefore, these reports 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: 20145306, 25487149, 33740630, 35339733, 32770674). ClinVar contains an entry for this variant (Variation ID: 251881). Based on the evidence outlined above, the variant was classified as uncertain significance. -
not provided Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingARUP Laboratories, Molecular Genetics and Genomics, ARUP LaboratoriesJan 11, 2021- -
Cardiovascular phenotype Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingAmbry GeneticsJul 18, 2018The p.V506M variant (also known as c.1516G>A), located in coding exon 10 of the LDLR gene, results from a G to A substitution at nucleotide position 1516. The valine at codon 506 is replaced by methionine, an amino acid with highly similar properties. This variant has been reported in one individual from an early myocardial infarction cohort, as well as in an individual with familial hypercholesterolemia (FH), who had an additional LDLR variant; however, clinical details were limited in both cases (Chmara M et al. J. Appl. Genet., 2010;51:95-106; Do R et al. Nature, 2015 Feb;518:102-6). Based on data from gnomAD, the A allele has an overall frequency of approximately 0.007% (17/246252) total alleles studied. The highest observed frequency was 0.075% (13/17248) of East Asian alleles. This amino acid position is poorly conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.088
BayesDel_addAF
Benign
-0.29
T
BayesDel_noAF
Benign
-0.28
CADD
Benign
1.0
DANN
Benign
0.93
DEOGEN2
Uncertain
0.51
D;.;.;.;.;.
Eigen
Benign
-1.2
Eigen_PC
Benign
-1.3
FATHMM_MKL
Benign
0.24
N
LIST_S2
Benign
0.29
T;T;T;T;T;T
M_CAP
Uncertain
0.15
D
MetaRNN
Benign
0.21
T;T;T;T;T;T
MetaSVM
Uncertain
-0.20
T
MutationAssessor
Benign
0.69
N;.;.;.;.;N
MutationTaster
Benign
1.0
N;N;N;N;N;N;N
PrimateAI
Benign
0.28
T
PROVEAN
Benign
-0.41
N;N;N;N;N;N
REVEL
Pathogenic
0.76
Sift
Benign
0.12
T;T;T;T;T;T
Sift4G
Benign
0.21
T;T;T;T;T;T
Polyphen
0.57
P;.;.;.;.;.
Vest4
0.30
MVP
0.97
MPC
0.24
ClinPred
0.047
T
GERP RS
-7.3
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.1
Varity_R
0.12
gMVP
0.84

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.0
Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs373848925; hg19: chr19-11224368; COSMIC: COSV52942560; COSMIC: COSV52942560; API