rs10417394

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP4BP7BS1

This summary comes from the ClinGen Evidence Repository: The NM_000527.5(LDLR):c.498C>T (p.Ala166=) variant is classified as Likely Benign for Familial Hypercholesterolemia by applying ACMG/AMP evidence codes BS1, BP4 and BP7 as defined by the ClinGen Familial Hypercholesterolemia Expert Panel LDLR-specific variant curation guidelines (spcification version 1.2) on 30 August 2024. The supporting evidence is as follows: BS1: FAF=0.004221 (0.42%) in African/African American exomes + genomes (gnomAD v4.1.0). BP4: No REVEL, splicing evaluation required. Functional data on splicing not available. A) not on limits. B) does not create a GT. C) there is a GT nearby. MES scores: variant cryptic = -2.92, wt cryptic = -2.92, canonical donor = 7.67. Cryptic scores are negative, so cryptic site is not used - variant is not predicted to alter splicing. BP7: Variant is synonymous and meets BP4. LINK:https://erepo.genome.network/evrepo/ui/classification/CA043710/MONDO:0007750/013

Frequency

Genomes: 𝑓 0.0014 ( 0 hom., cov: 33)
Exomes 𝑓: 0.00013 ( 1 hom. )

Consequence

LDLR
ENST00000558518.6 synonymous

Scores

2

Clinical Significance

Likely benign reviewed by expert panel U:1B:7

Conservation

PhyloP100: -0.354
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]

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ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -6 ACMG points.

BP4
For more information check the summary or visit ClinGen Evidence Repository.
BP7
For more information check the summary or visit ClinGen Evidence Repository.
BS1
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.498C>T p.Ala166= synonymous_variant 4/18 ENST00000558518.6 NP_000518.1

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
LDLRENST00000558518.6 linkuse as main transcriptc.498C>T p.Ala166= synonymous_variant 4/181 NM_000527.5 ENSP00000454071 P3P01130-1

Frequencies

GnomAD3 genomes
AF:
0.00141
AC:
214
AN:
152246
Hom.:
0
Cov.:
33
show subpopulations
Gnomad AFR
AF:
0.00492
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.000524
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.0000147
Gnomad OTH
AF:
0.000478
GnomAD3 exomes
AF:
0.000358
AC:
90
AN:
251292
Hom.:
0
AF XY:
0.000294
AC XY:
40
AN XY:
135880
show subpopulations
Gnomad AFR exome
AF:
0.00456
Gnomad AMR exome
AF:
0.000347
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.0000653
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.00
Gnomad OTH exome
AF:
0.000326
GnomAD4 exome
AF:
0.000126
AC:
184
AN:
1461690
Hom.:
1
Cov.:
33
AF XY:
0.000110
AC XY:
80
AN XY:
727156
show subpopulations
Gnomad4 AFR exome
AF:
0.00415
Gnomad4 AMR exome
AF:
0.000335
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.0000348
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.00
Gnomad4 OTH exome
AF:
0.000397
GnomAD4 genome
AF:
0.00143
AC:
218
AN:
152364
Hom.:
0
Cov.:
33
AF XY:
0.00140
AC XY:
104
AN XY:
74506
show subpopulations
Gnomad4 AFR
AF:
0.00500
Gnomad4 AMR
AF:
0.000523
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.0000147
Gnomad4 OTH
AF:
0.000473
Alfa
AF:
0.000671
Hom.:
0
Bravo
AF:
0.00145

ClinVar

Significance: Likely benign
Submissions summary: Uncertain:1Benign:7
Revision: reviewed by expert panel
LINK: link

Submissions by phenotype

Hypercholesterolemia, familial, 1 Uncertain:1Benign:2
Benign, no assertion criteria providedresearchLaboratorium voor Moleculaire Diagnostiek Experimentele Vasculaire Geneeskunde, Academisch Medisch Centrum-- -
Uncertain significance, criteria provided, single submitterclinical testingIllumina Laboratory Services, IlluminaJun 14, 2016- -
Likely benign, reviewed by expert panelcurationClinGen Familial Hypercholesterolemia Variant Curation Expert PanelAug 30, 2024The NM_000527.5(LDLR):c.498C>T (p.Ala166=) variant is classified as Likely Benign for Familial Hypercholesterolemia by applying ACMG/AMP evidence codes BS1, BP4 and BP7 as defined by the ClinGen Familial Hypercholesterolemia Expert Panel LDLR-specific variant curation guidelines (spcification version 1.2) on 30 August 2024. The supporting evidence is as follows: BS1: FAF=0.004221 (0.42%) in African/African American exomes + genomes (gnomAD v4.1.0). BP4: No REVEL, splicing evaluation required. Functional data on splicing not available. A) not on limits. B) does not create a GT. C) there is a GT nearby. MES scores: variant cryptic = -2.92, wt cryptic = -2.92, canonical donor = 7.67. Cryptic scores are negative, so cryptic site is not used - variant is not predicted to alter splicing. BP7: Variant is synonymous and meets BP4. -
Familial hypercholesterolemia Benign:3
Benign, criteria provided, single submitterclinical testingColor Diagnostics, LLC DBA Color HealthJul 17, 2017- -
Benign, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpFeb 01, 2024- -
Likely benign, no assertion criteria providedclinical testingNatera, Inc.Oct 25, 2019- -
not provided Benign:1
Benign, criteria provided, single submitterclinical testingQuest Diagnostics Nichols Institute San Juan CapistranoMar 07, 2023- -
Cardiovascular phenotype Benign:1
Likely benign, criteria provided, single submitterclinical testingAmbry GeneticsDec 27, 2017This 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
BayesDel_noAF
Benign
-0.42
CADD
Benign
5.3
DANN
Benign
0.78

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: rs10417394; hg19: chr19-11216080; API