chr19-11110735-G-A

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP4BA1

This summary comes from the ClinGen Evidence Repository: The NM_000527.5(LDLR):c.1024G>A (p.Asp342Asn) variant is classified as Benign for Familial Hypercholesterolemia by applying evidence codes (BA1 and BP4) as defined by the ClinGen Familial Hypercholesterolemia Expert Panel LDLR-specific variant curation guidelines (https://doi.org/10.1101/2021.03.17.21252755). The supporting evidence is as follows: BA1 - FAF = 0.005579 (0.56%) in African exomes (gnomAD v2.1.1). It is above 0.5%, so BA1 is met.BP4 - REVEL = 0.283. it is below 0.50, splicing evaluation required. Functional data on splicing not available. A) not on limits B) variant is exonic and at least 50bp downstream from canonical acceptor site but it does not create GT. Variant is not predicted to alter splicing, so BP4 is met. LINK:https://erepo.genome.network/evrepo/ui/classification/CA023404/MONDO:0007750/013

Frequency

Genomes: đť‘“ 0.0016 ( 1 hom., cov: 32)
Exomes đť‘“: 0.00016 ( 3 hom. )

Consequence

LDLR
NM_000527.5 missense

Scores

3
16

Clinical Significance

Benign reviewed by expert panel P:1U:4B:12O:1

Conservation

PhyloP100: 0.471
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 Benign. Variant got -9 ACMG points.

BP4
For more information check the summary or visit ClinGen Evidence Repository.
BA1
For more information check the summary or visit ClinGen Evidence Repository.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
LDLRNM_000527.5 linkc.1024G>A p.Asp342Asn missense_variant Exon 7 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.1024G>A p.Asp342Asn missense_variant Exon 7 of 18 1 NM_000527.5 ENSP00000454071.1 P01130-1

Frequencies

GnomAD3 genomes
AF:
0.00160
AC:
243
AN:
152180
Hom.:
1
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.00550
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.000590
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.000207
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.0000294
Gnomad OTH
AF:
0.00144
GnomAD3 exomes
AF:
0.000454
AC:
114
AN:
251038
Hom.:
2
AF XY:
0.000331
AC XY:
45
AN XY:
135788
show subpopulations
Gnomad AFR exome
AF:
0.00659
Gnomad AMR exome
AF:
0.000173
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.00000881
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.000165
AC:
241
AN:
1461476
Hom.:
3
Cov.:
31
AF XY:
0.000150
AC XY:
109
AN XY:
727044
show subpopulations
Gnomad4 AFR exome
AF:
0.00574
Gnomad4 AMR exome
AF:
0.000246
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.0000198
Gnomad4 OTH exome
AF:
0.000265
GnomAD4 genome
AF:
0.00160
AC:
243
AN:
152298
Hom.:
1
Cov.:
32
AF XY:
0.00138
AC XY:
103
AN XY:
74456
show subpopulations
Gnomad4 AFR
AF:
0.00548
Gnomad4 AMR
AF:
0.000589
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.000207
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.0000294
Gnomad4 OTH
AF:
0.00142
Alfa
AF:
0.0000953
Hom.:
0
Bravo
AF:
0.00189
ESP6500AA
AF:
0.00613
AC:
27
ESP6500EA
AF:
0.000116
AC:
1
ExAC
AF:
0.000651
AC:
79
Asia WGS
AF:
0.000289
AC:
1
AN:
3478
EpiCase
AF:
0.00
EpiControl
AF:
0.0000593

ClinVar

Significance: Benign
Submissions summary: Pathogenic:1Uncertain:4Benign:12Other:1
Revision: reviewed by expert panel
LINK: link

Submissions by phenotype

Hypercholesterolemia, familial, 1 Pathogenic:1Uncertain:1Benign:4
Dec 13, 2021
ClinGen Familial Hypercholesterolemia Variant Curation Expert Panel
Significance: Benign
Review Status: reviewed by expert panel
Collection Method: curation

The NM_000527.5(LDLR):c.1024G>A (p.Asp342Asn) variant is classified as Benign for Familial Hypercholesterolemia by applying evidence codes (BA1 and BP4) as defined by the ClinGen Familial Hypercholesterolemia Expert Panel LDLR-specific variant curation guidelines (https://doi.org/10.1101/2021.03.17.21252755). The supporting evidence is as follows: BA1 - FAF = 0.005579 (0.56%) in African exomes (gnomAD v2.1.1). It is above 0.5%, so BA1 is met. BP4 - REVEL = 0.283. it is below 0.50, splicing evaluation required. Functional data on splicing not available. A) not on limits B) variant is exonic and at least 50bp downstream from canonical acceptor site but it does not create GT. Variant is not predicted to alter splicing, so BP4 is met. -

Mar 01, 2016
Laboratory of Genetics and Molecular Cardiology, University of SĂŁo Paulo
Significance: Uncertain significance
Review Status: flagged submission
Collection Method: research

- -

Apr 27, 2017
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). No publications were found based on this search. Allele frequency data from public databases allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -

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

subject mutated among 2600 FH index cases screened = 1 / previously described in association with FH (linked to ethnicity ?) / Software predictions: Benign -

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

- -

-
Laboratorium voor Moleculaire Diagnostiek Experimentele Vasculaire Geneeskunde, Academisch Medisch Centrum
Significance: Pathogenic
Review Status: flagged submission
Collection Method: research

- -

not provided Uncertain:1Benign:3Other:1
-
Dept. of Genetics and Pharmacogenomics, Merck Research Labs
Significance: not provided
Review Status: no classification provided
Collection Method: in vitro

- -

Nov 21, 2024
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories
Significance: Benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

-
Department of Pathology and Laboratory Medicine, Sinai Health System
Significance: Uncertain significance
Review Status: flagged submission
Collection Method: clinical testing

The LDLR p.Asp301Asn variant was identified in dbSNP (ID: rs139361635) and in ClinVar (classified benign 2 times, likely benign 2 times, a VUS 4 times and pathogenic once). The variant was also identified in control databases in 168 of 282430 chromosomes (3 homozygous) at a frequency of 0.000595 increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: African in 160 of 24944 chromosomes (freq: 0.006414), Latino in 6 of 35432 chromosomes (freq: 0.000169), Other in 1 of 7220 chromosomes (freq: 0.000139) and European (non-Finnish) in 1 of 128970 chromosomes (freq: 0.000008), but not in the Ashkenazi Jewish, East Asian, European (Finnish) or South Asian populations. The D301N variant in LDLR has been reported in 4 individuals with possible or definitive hypercholesterolemia (Do_1997_PMID:25487149; Fouchier_2001_PMID:11810272; Sjouke_2015_PMID:24585268; Leigh_2008_PMID:18325082). The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) do not predict a difference in splicing. The p.Asp301 residue is not conserved in mammals and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) do not suggest a high likelihood of impact to the protein; however, this information is not predictive enough to rule out pathogenicity. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of uncertain significance. -

-
Breakthrough Genomics, Breakthrough Genomics
Significance: Likely benign
Review Status: criteria provided, single submitter
Collection Method: not provided

- -

Nov 13, 2024
GeneDx
Significance: Benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

See Variant Classification Assertion Criteria. -

Familial hypercholesterolemia Benign:3
Mar 11, 2018
Color Diagnostics, LLC DBA Color Health
Significance: Likely benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Oct 25, 2024
Labcorp Genetics (formerly Invitae), Labcorp
Significance: Benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Jul 09, 2024
GENinCode PLC
Significance: Benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

BA1 -

not specified Uncertain:1Benign:1
Nov 29, 2021
Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Significance: Benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

Variant summary: LDLR c.1024G>A (p.Asp342Asn) results in a conservative amino acid change located in the EGF-like domain (IPR000742) 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 0.00061 in 292610 control chromosomes, predominantly at a frequency of 0.0064 within the African or African-American subpopulation in the gnomAD database, including 3 homozygotes. The observed variant frequency within African or African-American control individuals in the gnomAD database is approximately 5-fold of the estimated maximal expected allele frequency for a pathogenic variant in LDLR causing Familial Hypercholesterolemia phenotype (0.0013), strongly suggesting that the variant is a benign polymorphism found primarily in populations of African or African-American origin. c.1024G>A has been reported in the literature in individuals with hypercholesterolemia, however it was also found in healthy controls (e.g. Do_2015). These reports do not provide unequivocal conclusions about association of the variant with Familial Hypercholesterolemia. At least one publication reports experimental evidence evaluating an impact on protein function, and demonstrated normal activities for this variant (Guo_2019). Eight clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation, and reported the variant with conflicting assessments (i.e. VUS (n=3), likely benign (n=3) / benign (n=2)). Based on the evidence outlined above, the variant was classified as benign. -

Jan 19, 2016
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

Variant classified as Uncertain Significance - Favor Benign. The p.Asp342Asn var iant in LDLR has been reported in 3 individuals with possible or definitive hype rcholesterolemia (Do 1997, Fouchier 2001, Sjouke 2015), including in one individ ual with a second LDLR variant. However, this variant has also been identified i n 0.6% (160/24944) of African chromosomes by the Genome Aggregation Consortium ( gnomAD, http://exac.broadinstitute.org). Computational prediction tools and cons ervation analysis suggest that the variant may not impact the protein, though th is information is not predictive enough to rule out pathogenicity. In summary, w hile the clinical significance of the p.Asp342Asn variant is uncertain, its freq uency suggests that it is more likely to be benign. ACMG/AMP Criteria applied: P S4_Supporting, BS1, BP4. -

Hypercholesterolemia Uncertain:1
Jun 01, 2014
CSER _CC_NCGL, University of Washington
Significance: Uncertain significance
Review Status: flagged submission
Collection Method: research

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

Cardiovascular phenotype Benign:1
Oct 30, 2017
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
0.071
BayesDel_addAF
Benign
-0.30
T
BayesDel_noAF
Benign
-0.20
CADD
Benign
8.3
DANN
Benign
0.97
DEOGEN2
Uncertain
0.58
D;.;.;.;.;.
Eigen
Benign
-1.0
Eigen_PC
Benign
-1.0
FATHMM_MKL
Benign
0.58
D
LIST_S2
Benign
0.76
T;T;T;T;T;T
M_CAP
Uncertain
0.28
D
MetaRNN
Benign
0.043
T;T;T;T;T;T
MetaSVM
Uncertain
-0.25
T
MutationAssessor
Benign
0.16
N;.;.;.;.;N
PrimateAI
Benign
0.21
T
PROVEAN
Benign
-0.96
N;N;N;N;N;N
REVEL
Benign
0.28
Sift
Benign
0.34
T;T;T;T;T;T
Sift4G
Benign
0.13
T;T;T;T;T;T
Polyphen
0.0
B;.;.;.;.;.
Vest4
0.19
MVP
1.0
MPC
0.21
ClinPred
0.0055
T
GERP RS
-0.69
Varity_R
0.22
gMVP
0.85

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: rs139361635; hg19: chr19-11221411; API