chr19-11110735-G-A

Variant names:

• chr19-11110735-G-A
• rs139361635
• NM_000527.5:c.1024G>A

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP4 BA1

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: 𝑓 0.0016 (1 hom., cov: 32)
  • Exomes 𝑓: 0.00016 (3 hom.)
• Consequence: LDLR NM_000527.5 missense
• Clinical Significance: Benign reviewed by expert panel P:1 U:4 B:12 O:1
• Conservation: PhyloP100: 0.471

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]

ACMG classification

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
LDLR	NM_000527.5	c.1024G>A	p.Asp342Asn	missense_variant	Exon 7 of 18	ENST00000558518.6	NP_000518.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
LDLR	ENST00000558518.6	c.1024G>A	p.Asp342Asn	missense_variant	Exon 7 of 18	1	NM_000527.5	ENSP00000454071.1

Frequencies

GnomAD3 genomes AF: 0.00160 AC: 243 AN: 152180 Hom.: 1 Cov.: 32

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

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

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

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:1 Uncertain:4 Benign:12 Other:1

Revision: reviewed by expert panel

Submissions by phenotype

Hypercholesterolemia, familial, 1 Pathogenic:1 Uncertain:1 Benign:4

Mar 01, 2016

Laboratory of Genetics and Molecular Cardiology, University of São 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 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. -

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:1 Benign:3 Other:1

-

Dept. of Genetics and Pharmacogenomics, Merck Research Labs

Significance: not provided

Review Status: no classification provided

Collection Method: in vitro

- -

Nov 13, 2024

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

See Variant Classification Assertion Criteria. -

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

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. -

Familial hypercholesterolemia Benign:3

Jul 09, 2024

GENinCode PLC

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

BA1 -

Oct 25, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Mar 11, 2018

Color Diagnostics, LLC DBA Color Health

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not specified Uncertain:1 Benign:1

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. -

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. -

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

Other links and lift over

dbSNP: rs139361635; hg19: chr19-11221411;