NM_000527.5:c.940G>A

Variant names:

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM1PP2PP3

The NM_000527.5(LDLR):c.940G>A(p.Gly314Arg) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000442 in 1,606,422 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 2/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G314W) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.000046 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000044 ( 0 hom. )

Consequence

LDLR
NM_000527.5 missense, splice_region

Scores

Splicing: ADA: 0.9786

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1U:12O:1

Conservation

PhyloP100: 1.10

Publications

10 publications found

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]

LDLR Gene-Disease associations (from GenCC):

hypercholesterolemia, familial, 1
Inheritance: AD, SD Classification: DEFINITIVE, STRONG Submitted by: Genomics England PanelApp, Labcorp Genetics (formerly Invitae), Laboratory for Molecular Medicine, ClinGen
homozygous familial hypercholesterolemia
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

LDLR links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 4 ACMG points.

PM1

In a hotspot region, there are 23 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 13 uncertain in NM_000527.5

PP2

Missense variant in the gene, where a lot of missense mutations are associated with disease in ClinVar. The gene has 678 curated pathogenic missense variants (we use a threshold of 10). The gene has 92 curated benign missense variants. Gene score misZ: 0.12407 (below the threshold of 3.09). Trascript score misZ: 0.59338 (below the threshold of 3.09). GenCC associations: The gene is linked to hypercholesterolemia, familial, 1, homozygous familial hypercholesterolemia.

PP3

Splicing predictors support a deleterious effect. Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF. No scorers claiming Uncertain. Scorers claiming Benign: max_spliceai.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
LDLR	NM_000527.5 link	c.940G>A	p.Gly314Arg	missense_variant, splice_region_variant	Exon 6 of 18	ENST00000558518.6	NP_000518.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
LDLR	ENST00000558518.6 link	c.940G>A	p.Gly314Arg	missense_variant, splice_region_variant	Exon 6 of 18	1	NM_000527.5	ENSP00000454071.1

Frequencies

GnomAD3 genomes

AF:

0.0000460

AC:

AN:

152040

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000483

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000193

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000588

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000478

AC:

AN:

250802

AF XY:

0.0000443

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000578

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000706

Gnomad OTH exome

AF:

0.000163

GnomAD4 exome

AF:

0.0000440

AC:

AN:

1454264

Hom.:

Cov.:

AF XY:

0.0000428

AC XY:

AN XY:

723526

show subpopulations

African (AFR)

AF:

0.0000902

AC:

AN:

33256

American (AMR)

AF:

0.0000450

AC:

AN:

44462

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25842

East Asian (EAS)

AF:

0.00

AC:

AN:

39302

South Asian (SAS)

AF:

0.0000232

AC:

AN:

86120

European-Finnish (FIN)

AF:

0.00

AC:

AN:

52620

Middle Eastern (MID)

AF:

0.00105

AC:

AN:

5740

European-Non Finnish (NFE)

AF:

0.0000397

AC:

AN:

1107060

Other (OTH)

AF:

0.000117

AC:

AN:

59862

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.457

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0000460

AC:

AN:

152158

Hom.:

Cov.:

AF XY:

0.0000538

AC XY:

AN XY:

74402

show subpopulations

African (AFR)

AF:

0.0000482

AC:

AN:

41528

American (AMR)

AF:

0.00

AC:

AN:

15240

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.000193

AC:

AN:

5172

South Asian (SAS)

AF:

0.00

AC:

AN:

4816

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10616

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0000588

AC:

AN:

67998

Other (OTH)

AF:

0.00

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.518

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.000138

Hom.:

Bravo

AF:

0.0000680

TwinsUK

AF:

0.00

AC:

ALSPAC

AF:

0.000259

AC:

ExAC

AF:

0.0000412

AC:

EpiCase

AF:

0.000109

EpiControl

AF:

0.000119

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1Uncertain:12Other:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Hypercholesterolemia, familial, 1

Uncertain:4

Aug 06, 2024

All of Us Research Program, National Institutes of Health

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This missense variant (also known as p.Gly293Arg in the mature protein) replaces glycine with arginine at codon 314 of the LDLR protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). A functional study has shown the mutant protein to show normal protein maturation and plasma membrane localization (Khalid Jawabri 2020, dissertation, United Arab Emirates University). This variant has been reported in several individuals affected with premature atherosclerosis and/or familial hypercholesterolemia in the literature (PMID: 17347910, 33794673). This variant has been identified in 13/282176 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. -

Oct 26, 2021

Fulgent Genetics, Fulgent Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Mar 26, 2024

Genomic Medicine Center of Excellence, King Faisal Specialist Hospital and Research Centre

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Mar 25, 2016

LDLR-LOVD, British Heart Foundation

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:literature only

- -

Familial hypercholesterolemia

Pathogenic:1Uncertain:2

Sep 16, 2020

Natera, Inc.

Significance:Uncertain significance

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Feb 20, 2024

Color Diagnostics, LLC DBA Color Health

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This missense variant replaces glycine with arginine at codon 314 of the LDLR protein. This variant is also known as p.Gly293Arg in the mature protein. Computational prediction tools indicate that this variant's impact on protein structure and function is inconclusive. A functional study has shown the mutant protein to show normal protein maturation and plasma membrane localization (Khalid Jawabri 2020, dissertation, United Arab Emirates University). This variant has been reported in several individuals affected with premature atherosclerosis and/or familial hypercholesterolemia in the literature (PMID: 17347910, 33794673). This variant has been identified in 13/282176 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. -

Aug 26, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This sequence change replaces glycine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 314 of the LDLR protein (p.Gly314Arg). This variant also falls at the last nucleotide of exon 6, which is part of the consensus splice site for this exon. This variant is present in population databases (rs72658858, gnomAD 0.006%). This missense change has been observed in individuals with familial hypercholesterolemia (PMID: 17347910, 28104544, 28349888, 33794673, 35047021). This variant is also known as G293R. ClinVar contains an entry for this variant (Variation ID: 183102). An algorithm developed to predict the effect of missense changes on protein structure and function outputs the following: PolyPhen-2: "Benign". The arginine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. -

not specified

Uncertain:3

May 04, 2022

Mendelics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

May 28, 2025

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Variant summary: LDLR c.940G>A (p.Gly314Arg) results in a non-conservative amino acid change in the encoded protein sequence. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change. As the variant affects the last conserved nucleotide of exon 6 adjacent to the intron 6 splice donor site, several computational tools predict a significant impact on normal splicing: Four predict the variant weakens a 5' donor site. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 4.8e-05 in 250802 control chromosomes (gnomAD). This frequency is not significantly higher than estimated for a pathogenic variant in LDLR causing Familial Hypercholesterolemia (4.8e-05 vs 0.0013), allowing no conclusion about variant significance. c.940G>A has been reported in the literature in individuals affected with Familial Hypercholesterolemia (example, Widhalm_2007, Durst_2017, Futema_2017, Rimbert_2021). These report(s) do not provide unequivocal conclusions about association of the variant with Familial Hypercholesterolemia. An in vitro functional study report that the variant had neutral effect on cellular LDL-uptake (Thormaehlen_2015). The following publications have been ascertained in the context of this evaluation (PMID: 28104544, 28349888, 35047021, 17347910, 25647241). ClinVar contains an entry for this variant (Variation ID: 183102). Based on the evidence outlined above, the variant was classified as uncertain significance. -

Jan 24, 2017

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: This variant is present in ExAC with a MaxMAF of 0.006%. This region is not conserved and 4 mammals and 1 non-mammal have an Arg at this position. It is predicted benign by all predictive tools. It is present in ClinVar with 1 star and classified as VUS by the British Heart Foundation. It is present in 3 patients with FH. -

not provided

Uncertain:2Other:1

Jan 29, 2024

Quest Diagnostics Nichols Institute San Juan Capistrano

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The LDLR c.940G>A (p.Gly314Arg) variant has been reported in the published literature in individuals with hypercholesterolemia (PMIDs: 33794673 (2021), 35047021 (2021), 28349888 (2017), 28104544 (2017), 17347910 (2007)). A functional study indicated this variant has neutral effect on cellular LDL-uptake efficiency (PMID: 25647241 (2015)). The frequency of this variant in the general population, 0.00007 (9/128680 chromosomes (Genome Aggregation Database, http://gnomad.broadinstitute.org)), is uninformative in the assessment of its pathogenicity. Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded conflicting predictions that this variant is deleterious or benign. Additional analysis using software algorithms for the prediction of the effect of nucleotide changes on splicing yielded predictions that this variant may affect proper LDLR mRNA splicing. Based on the available information, we are unable to determine the clinical significance of this variant. -

Dept. of Genetics and Pharmacogenomics, Merck Research Labs

Significance:not provided

Review Status:no classification provided

Collection Method:in vitro

- -

Breakthrough Genomics, Breakthrough Genomics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Cardiovascular phenotype

Uncertain:1

Aug 09, 2024

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The p.G314R variant (also known as c.940G>A), located in coding exon 6 of the LDLR gene, results from a G to A substitution at nucleotide position 940. The glycine at codon 314 is replaced by arginine, an amino acid with dissimilar properties. However, this change occurs in the last base pair of coding exon 6 and may have some effect on normal mRNA splicing. This variant (also described as legacy p.G293R) has been reported in hypercholesterolemia cohorts; however, clinical details were limited in many cases (Widhalm K et al. J Inherit Metab Dis, 2007 Apr;30:239-47; Durst R et al. Atherosclerosis, 2017 02;257:55-63; Futema M et al. Atherosclerosis, 2017 05;260:47-55; Turkyilmaz A et al. Metab Syndr Relat Disord, 2021 08;19:340-346). Limited functional analyses suggested no significant impact (Thormaehlen AS et al. PLoS Genet, 2015 Feb;11:e1004855). This nucleotide position is not well conserved in available vertebrate species. In silico splice site analysis predicts that this alteration will not have any significant effect on splicing. This amino acid position is not well conserved in available vertebrate species. In addition, as a missense substitution this is predicted to be deleterious by in silico analysis. Based on the available evidence, the clinical significance of this variant remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.22

BayesDel_addAF

Uncertain

0.15

BayesDel_noAF

Pathogenic

0.16

CADD

Benign

(source)

DANN

Uncertain

0.98

DEOGEN2

Uncertain

0.78

D;.;.;.;.;.

Eigen

Benign

-0.36

Eigen_PC

Benign

-0.32

FATHMM_MKL

Uncertain

0.91

LIST_S2

Benign

0.79

T;T;T;T;T;T

M_CAP

Pathogenic

0.67

MetaRNN

Benign

0.42

T;T;T;T;T;T

MetaSVM

Uncertain

-0.018

MutationAssessor

Pathogenic

3.4

M;.;.;.;.;M

PhyloP100

1.1

PrimateAI

Benign

0.26

PROVEAN

Uncertain

-3.5

D;D;D;D;D;D

REVEL

Uncertain

0.61

Sift

Benign

0.052

T;D;D;T;T;T

Sift4G

Benign

0.075

T;D;T;D;T;T

Polyphen

0.10

B;.;.;.;.;.

Vest4

0.29

MutPred

0.65

Loss of ubiquitination at K311 (P = 0.0584);Loss of ubiquitination at K311 (P = 0.0584);.;.;.;Loss of ubiquitination at K311 (P = 0.0584);

MVP

1.0

MPC

0.29

ClinPred

0.14

GERP RS

2.1

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

2.7

Varity_R

0.29

gMVP

0.81

Mutation Taster

=1/99

disease causing

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Pathogenic

0.98

dbscSNV1_RF

Pathogenic

0.75

SpliceAI score (max)

0.010

Details are displayed if max score is > 0.2

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over