Genetic Variant NM_000527.5:c.829G>A (chr19-11107403-G-A) – ACMG Classification: Likely_benign (-2 pts)

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 3P and 5B. PM1PP2BP4_StrongBP6

The NM_000527.5(LDLR):c.829G>A(p.Glu277Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000449 in 1,611,352 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 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. E277D) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.00037 ( 0 hom., cov: 31)

Exomes 𝑓: 0.00046 ( 0 hom. )

Consequence

LDLR
NM_000527.5 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:7B:19O:1

Conservation

PhyloP100: 2.64

Publications

25 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: Laboratory for Molecular Medicine, Labcorp Genetics (formerly Invitae), Genomics England PanelApp, 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: Likely_benign. The variant received -2 ACMG points.

PM1

In a hotspot region, there are 14 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 2 benign, 19 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.

BP4

Computational evidence support a benign effect (MetaRNN=0.05303049).

BP6

Variant 19-11107403-G-A is Benign according to our data. Variant chr19-11107403-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 183097.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000527.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
LDLR	NM_000527.5	MANE Select	c.829G>A	p.Glu277Lys	missense	Exon 6 of 18	NP_000518.1	P01130-1
LDLR	NM_001195798.2		c.829G>A	p.Glu277Lys	missense	Exon 6 of 18	NP_001182727.1	P01130-5
LDLR	NM_001195799.2		c.706G>A	p.Glu236Lys	missense	Exon 5 of 17	NP_001182728.1	P01130-4

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
LDLR	ENST00000558518.6	TSL:1 MANE Select	c.829G>A	p.Glu277Lys	missense	Exon 6 of 18	ENSP00000454071.1	P01130-1
LDLR	ENST00000252444.10	TSL:1	c.1087G>A	p.Glu363Lys	missense	Exon 6 of 18	ENSP00000252444.6	J3KMZ9
LDLR	ENST00000558013.5	TSL:1	c.829G>A	p.Glu277Lys	missense	Exon 6 of 18	ENSP00000453346.1	P01130-5

Frequencies

GnomAD3 genomes

AF:

0.000375

AC:

AN:

152062

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000169

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00131

Gnomad ASJ

AF:

0.000288

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00125

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000323

Gnomad OTH

AF:

0.000479

GnomAD2 exomes

AF:

0.000537

AC:

135

AN:

251424

AF XY:

0.000625

show subpopulations

Gnomad AFR exome

AF:

0.000308

Gnomad AMR exome

AF:

0.00107

Gnomad ASJ exome

AF:

0.000397

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000343

Gnomad OTH exome

AF:

0.000326

GnomAD4 exome

AF:

0.000457

AC:

667

AN:

1459172

Hom.:

Cov.:

AF XY:

0.000496

AC XY:

360

AN XY:

725900

show subpopulations

African (AFR)

AF:

0.000210

AC:

AN:

33388

American (AMR)

AF:

0.00108

AC:

AN:

44626

Ashkenazi Jewish (ASJ)

AF:

0.000422

AC:

AN:

26038

East Asian (EAS)

AF:

0.0000253

AC:

AN:

39536

South Asian (SAS)

AF:

0.00174

AC:

150

AN:

86204

European-Finnish (FIN)

AF:

0.0000188

AC:

AN:

53170

Middle Eastern (MID)

AF:

0.00139

AC:

AN:

5756

European-Non Finnish (NFE)

AF:

0.000365

AC:

405

AN:

1110252

Other (OTH)

AF:

0.000598

AC:

AN:

60202

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.479

Heterozygous variant carriers

129

172

215

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

100

<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:

0.000375

AC:

AN:

152180

Hom.:

Cov.:

AF XY:

0.000457

AC XY:

AN XY:

74402

show subpopulations

African (AFR)

AF:

0.000169

AC:

AN:

41526

American (AMR)

AF:

0.00131

AC:

AN:

15244

Ashkenazi Jewish (ASJ)

AF:

0.000288

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5182

South Asian (SAS)

AF:

0.00125

AC:

AN:

4810

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10608

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000323

AC:

AN:

68024

Other (OTH)

AF:

0.000474

AC:

AN:

2108

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.509

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:

0.000481

Hom.:

Bravo

AF:

0.000453

ESP6500AA

AF:

0.000227

AC:

ESP6500EA

AF:

0.000233

AC:

ExAC

AF:

0.000502

AC:

Asia WGS

AF:

0.000577

AC:

AN:

3478

EpiCase

AF:

0.000436

EpiControl

AF:

0.000533

ClinVar

ClinVar submissions

Significance:Conflicting classifications of pathogenicity

Revision:criteria provided, conflicting classifications

View on ClinVar

Pathogenic

VUS

Benign

Condition

Hypercholesterolemia, familial, 1 (11)

not specified (5)

Familial hypercholesterolemia (4)

not provided (5)

Cardiovascular phenotype (1)

LDLR-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.083

BayesDel_addAF

Benign

-0.16

BayesDel_noAF

Uncertain

-0.030

CADD

Benign

(source)

DANN

Uncertain

0.99

DEOGEN2

Uncertain

0.68

Eigen

Benign

-0.12

Eigen_PC

Benign

-0.025

FATHMM_MKL

Uncertain

0.95

LIST_S2

Uncertain

0.92

M_CAP

Pathogenic

0.42

MetaRNN

Benign

0.053

MetaSVM

Uncertain

0.38

MutationAssessor

Benign

1.3

PhyloP100

2.6

PrimateAI

Uncertain

0.48

PROVEAN

Benign

-2.2

REVEL

Uncertain

0.53

Sift

Benign

0.28

Sift4G

Benign

0.18

Polyphen

0.29

Vest4

0.42

MVP

1.0

MPC

0.37

ClinPred

0.022

GERP RS

5.3

Varity_R

0.41

gMVP

0.83

Mutation Taster

=30/70

disease causing (ClinVar)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over