19-11100303-G-T

Variant summary

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

This summary comes from the ClinGen Evidence Repository: The NM_000527.5(LDLR):c.148G>T (p.Ala50Ser) variant is classified as Uncertain significance - insufficient evidence for Familial Hypercholesterolemia by applying no ACMG/AMP evidence codes as defined by the ClinGen Familial Hypercholesterolemia Expert Panel LDLR-specific variant curation guidelines (specification version 1.2) on October 28th, 2024. LINK:https://erepo.genome.network/evrepo/ui/classification/CA023515/MONDO:0007750/013

Frequency

Genomes: 𝑓 0.00044 ( 0 hom., cov: 33)
Exomes 𝑓: 0.00063 ( 0 hom. )

Consequence

LDLR
NM_000527.5 missense

Scores

4
15

Clinical Significance

Uncertain significance reviewed by expert panel U:6B:19O:1

Conservation

PhyloP100: -0.218
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 0 ACMG points.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
LDLRNM_000527.5 linkc.148G>T p.Ala50Ser missense_variant Exon 2 of 18 ENST00000558518.6 NP_000518.1 P01130-1A0A024R7D5

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
LDLRENST00000558518.6 linkc.148G>T p.Ala50Ser missense_variant Exon 2 of 18 1 NM_000527.5 ENSP00000454071.1 P01130-1

Frequencies

GnomAD3 genomes
AF:
0.000440
AC:
67
AN:
152158
Hom.:
0
Cov.:
33
show subpopulations
Gnomad AFR
AF:
0.000145
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.000328
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.0000943
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.000794
Gnomad OTH
AF:
0.000478
GnomAD3 exomes
AF:
0.000530
AC:
133
AN:
251180
Hom.:
0
AF XY:
0.000538
AC XY:
73
AN XY:
135740
show subpopulations
Gnomad AFR exome
AF:
0.000185
Gnomad AMR exome
AF:
0.000491
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.0000933
Gnomad NFE exome
AF:
0.000968
Gnomad OTH exome
AF:
0.000163
GnomAD4 exome
AF:
0.000632
AC:
923
AN:
1461492
Hom.:
0
Cov.:
31
AF XY:
0.000597
AC XY:
434
AN XY:
727038
show subpopulations
Gnomad4 AFR exome
AF:
0.0000896
Gnomad4 AMR exome
AF:
0.000581
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.000263
Gnomad4 NFE exome
AF:
0.000773
Gnomad4 OTH exome
AF:
0.000348
GnomAD4 genome
AF:
0.000440
AC:
67
AN:
152276
Hom.:
0
Cov.:
33
AF XY:
0.000443
AC XY:
33
AN XY:
74450
show subpopulations
Gnomad4 AFR
AF:
0.000144
Gnomad4 AMR
AF:
0.000327
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.0000943
Gnomad4 NFE
AF:
0.000794
Gnomad4 OTH
AF:
0.000473
Alfa
AF:
0.000230
Hom.:
0
Bravo
AF:
0.000442
TwinsUK
AF:
0.000270
AC:
1
ALSPAC
AF:
0.00104
AC:
4
ESP6500AA
AF:
0.000227
AC:
1
ESP6500EA
AF:
0.000698
AC:
6
ExAC
AF:
0.000651
AC:
79
EpiCase
AF:
0.000436
EpiControl
AF:
0.000652

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:6Benign:19Other:1
Revision: reviewed by expert panel
LINK: link

Submissions by phenotype

Hypercholesterolemia, familial, 1 Uncertain:3Benign:10
Mar 01, 2016
Fundacion Hipercolesterolemia Familiar
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: research

- -

Mar 30, 2017
U4M - Lille University & CHRU Lille, Université de Lille - CHRU de Lille
Significance: Likely benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

ACMG Guidelines: Pathogenic (ii) -

Aug 31, 2015
Cardiovascular Biomarker Research Laboratory, Mayo Clinic
Significance: Likely benign
Review Status: criteria provided, single submitter
Collection Method: research

MAF =<0.3% -

Mar 25, 2016
LDLR-LOVD, British Heart Foundation
Significance: Benign
Review Status: criteria provided, single submitter
Collection Method: literature only

- -

Dec 16, 2016
Centre de Génétique Moléculaire et Chromosomique, Unité de génétique de l'Obésité et des Dyslipidémies, APHP, GH Hôpitaux Universitaires Pitié-Salpêtrière / Charles-Foix
Significance: Benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

subjects mutated among 2600 FH index cases screened = 4 , 2 compound heterozygous / Software predictions: Benign -

Mar 16, 2017
Molecular Genetics Laboratory, Centre for Cardiovascular Surgery and Transplantation
Significance: Benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Aug 22, 2019
Robarts Research Institute, Western University
Significance: Likely benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

-
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen
Significance: Benign
Review Status: no assertion criteria provided
Collection Method: clinical testing

- -

-
Laboratorium voor Moleculaire Diagnostiek Experimentele Vasculaire Geneeskunde, Academisch Medisch Centrum
Significance: Benign
Review Status: no assertion criteria provided
Collection Method: research

- -

Feb 04, 2019
Institute of Human Genetics, University of Leipzig Medical Center
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Oct 28, 2024
ClinGen Familial Hypercholesterolemia Variant Curation Expert Panel
Significance: Uncertain significance
Review Status: reviewed by expert panel
Collection Method: curation

The NM_000527.5(LDLR):c.148G>T (p.Ala50Ser) variant is classified as Uncertain significance - insufficient evidence for Familial Hypercholesterolemia by applying no ACMG/AMP evidence codes as defined by the ClinGen Familial Hypercholesterolemia Expert Panel LDLR-specific variant curation guidelines (specification version 1.2) on October 28th, 2024. -

Sep 07, 2018
Illumina Laboratory Services, Illumina
Significance: Likely benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

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). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to determine this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -

Sep 23, 2024
All of Us Research Program, National Institutes of Health
Significance: Likely benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

not specified Uncertain:1Benign:3
-
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center
Significance: Benign
Review Status: no assertion criteria provided
Collection Method: clinical testing

- -

Apr 18, 2025
Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Significance: Likely benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

Variant summary: LDLR c.148G>T (p.Ala50Ser; also known as p.Ala29Ser) results in a conservative amino acid change located in the first class A repeat domain (IPR002172) of 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 0.00054 in 262944 control chromosomes, predominantly at a frequency of 0.00097 within the Non-Finnish European subpopulation in the gnomAD database. However, in certain European regions the variant was found with a higher allele frequency, e.g. in the Swedish (0.0018), which is higher than estimated maximum expected for a pathogenic variant in LDLR causing Familial Hypercholesterolemia (0.0013), suggesting that the variant might be benign. The variant, c.148G>T, has been reported in the literature in individuals affected with hypercholesterolemia, however it was also found in controls and individuals with low LDL cholesterol (Ahmad_2012, Beaudoin_2012, Brusgaard_2006, Chmarra_2010, Do_2015, Ebhardt_1999, Fouchier_2001, Jensen_1994, Junyent_2010, Koeijvoets_2005, Lange_2014, Leren_2004, Tejedor_2010, Geller_2018, Sustar_2022). These reports do not provide unequivocal conclusions about association of the variant with Familial Hypercholesterolemia. In a family the variant was found to not segregate with disease (Jensen_1994). In addition, co-occurrences with other pathogenic variants have been reported (e.g. LDLR c.12G>A (p.Trp4X); Tejedor_2010 and LDLR c.1033C>T (p.Gln345X) in an internal LCA sample), providing supporting evidence for a benign role. 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: 23064986, 22923420, 16542394, 20145306, 25487149, 24055113, 10090484, 11810272, 30333156, 7820934, 19717150, 15823280, 24507775, 15199436, 10735632, 24956927, 28145427, 35913489, 20428891). ClinVar contains an entry for this variant (Variation ID: 68099). Based on the evidence outlined above, the variant was classified as likely benign. -

Mar 31, 2016
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: 5 papers describe as VUS/nonpathogenic; ExAC: 0.1% (67/66532) European; ClinVar: 1 VUS -

-
Clinical Genetics, Academic Medical Center
Significance: Benign
Review Status: no assertion criteria provided
Collection Method: clinical testing

- -

not provided Uncertain:1Benign:2Other:1
-
SNPedia
Significance: not provided
Review Status: no classification provided
Collection Method: literature only

- -

Feb 17, 2020
Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Jul 20, 2020
GeneDx
Significance: Likely benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

This variant is associated with the following publications: (PMID: 27044878, 30333156, 7820934, 20506408, 18325082, 16542394, 15576851, 10090484, 26332594, 25487149, 25637381, 22390909, 24055113) -

Jul 26, 2022
Quest Diagnostics Nichols Institute San Juan Capistrano
Significance: Likely benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Familial hypercholesterolemia Benign:2
Jan 30, 2025
Labcorp Genetics (formerly Invitae), Labcorp
Significance: Likely benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Nov 23, 2017
Color Diagnostics, LLC DBA Color Health
Significance: Likely benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Hypercholesterolemia Uncertain:1
Jun 01, 2014
CSER _CC_NCGL, University of Washington
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: research

Low GERP score may suggest that this variant may belong in a lower pathogenicity class -

LDLR-related disorder Benign:1
Jun 18, 2019
PreventionGenetics, part of Exact Sciences
Significance: Likely benign
Review Status: no assertion criteria provided
Collection Method: clinical testing

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Cardiovascular phenotype Benign:1
Jan 22, 2019
Ambry Genetics
Significance: Likely benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

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

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.082
BayesDel_addAF
Benign
-0.079
T
BayesDel_noAF
Uncertain
0.060
CADD
Benign
0.058
DANN
Benign
0.83
DEOGEN2
Uncertain
0.46
T;.;.;.;.;.
Eigen
Benign
-1.3
Eigen_PC
Benign
-1.4
FATHMM_MKL
Benign
0.29
N
LIST_S2
Benign
0.76
T;T;T;D;T;T
M_CAP
Benign
0.084
D
MetaRNN
Benign
0.047
T;T;T;T;T;T
MetaSVM
Uncertain
-0.12
T
MutationAssessor
Benign
0.77
N;.;N;N;N;N
PrimateAI
Benign
0.25
T
PROVEAN
Benign
-0.28
N;N;N;N;N;N
REVEL
Uncertain
0.55
Sift
Benign
0.32
T;T;T;T;T;T
Sift4G
Benign
0.49
T;T;T;T;T;T
Polyphen
0.014
B;.;.;.;.;.
Vest4
0.12
MVP
1.0
MPC
0.23
ClinPred
0.010
T
GERP RS
-5.7
RBP_binding_hub_radar
0.97
RBP_regulation_power_radar
2.8
Varity_R
0.098
gMVP
0.83

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: rs137853960; hg19: chr19-11210979; API