rs121908035

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Pathogenic. The variant received 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong

The NM_000527.5(LDLR):c.693C>A(p.Cys231*) variant causes a stop gained, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000298 in 1,344,082 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely pathogenic (★★). Synonymous variant affecting the same amino acid position (i.e. C231C) has been classified as Likely benign. Variant results in nonsense mediated mRNA decay.

Frequency

Genomes: 𝑓 0.0000067 ( 0 hom., cov: 33)

Exomes 𝑓: 0.0000025 ( 0 hom. )

Consequence

LDLR
NM_000527.5 stop_gained, splice_region

Scores

Splicing: ADA: 0.00009398

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:14

Conservation

PhyloP100: -0.338

Publications

8 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: Pathogenic. The variant received 18 ACMG points.

PVS1

Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.

PM2

Very rare variant in population databases, with high coverage;

PP5

Variant 19-11105599-C-A is Pathogenic according to our data. Variant chr19-11105599-C-A is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 3730.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

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.693C>A	p.Cys231*	stop_gained splice_region	Exon 4 of 18	NP_000518.1	P01130-1
LDLR	NM_001195798.2		c.693C>A	p.Cys231*	stop_gained splice_region	Exon 4 of 18	NP_001182727.1	P01130-5
LDLR	NM_001195799.2		c.570C>A	p.Cys190*	stop_gained splice_region	Exon 3 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.693C>A	p.Cys231*	stop_gained splice_region	Exon 4 of 18	ENSP00000454071.1	P01130-1
LDLR	ENST00000252444.10	TSL:1	c.951C>A	p.Cys317*	stop_gained splice_region	Exon 4 of 18	ENSP00000252444.6	J3KMZ9
LDLR	ENST00000558013.5	TSL:1	c.693C>A	p.Cys231*	stop_gained splice_region	Exon 4 of 18	ENSP00000453346.1	P01130-5

Frequencies

GnomAD3 genomes

AF:

0.00000667

AC:

AN:

150004

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

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:

0.0000148

Gnomad OTH

AF:

0.00

GnomAD4 exome

AF:

0.00000251

AC:

AN:

1194078

Hom.:

Cov.:

AF XY:

0.00000334

AC XY:

AN XY:

598810

show subpopulations

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.00

AC:

AN:

28076

American (AMR)

AF:

0.00

AC:

AN:

42224

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

22420

East Asian (EAS)

AF:

0.00

AC:

AN:

32986

South Asian (SAS)

AF:

0.00

AC:

AN:

81182

European-Finnish (FIN)

AF:

0.00

AC:

AN:

42404

Middle Eastern (MID)

AF:

0.00

AC:

AN:

3962

European-Non Finnish (NFE)

AF:

0.00000336

AC:

AN:

891660

Other (OTH)

AF:

0.00

AC:

AN:

49164

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.0225104), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.375

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:

0.00000667

AC:

AN:

150004

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

73278

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41090

American (AMR)

AF:

0.00

AC:

AN:

15078

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3448

East Asian (EAS)

AF:

0.00

AC:

AN:

4904

South Asian (SAS)

AF:

0.00

AC:

AN:

4592

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10058

Middle Eastern (MID)

AF:

0.00

AC:

AN:

314

European-Non Finnish (NFE)

AF:

0.0000148

AC:

AN:

67544

Other (OTH)

AF:

0.00

AC:

AN:

2082

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.425

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.0000272

Hom.:

Bravo

AF:

0.00000378

ClinVar

ClinVar submissions

Significance:Pathogenic/Likely pathogenic

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

Hypercholesterolemia, familial, 1 (10)

Familial hypercholesterolemia (3)

Cardiovascular phenotype (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Pathogenic

0.63

BayesDel_noAF

Pathogenic

0.23

CADD

Pathogenic

(source)

DANN

Uncertain

0.98

Eigen

Benign

-0.35

Eigen_PC

Benign

-0.71

FATHMM_MKL

Uncertain

0.80

PhyloP100

-0.34

Vest4

0.85

GERP RS

-2.4

PromoterAI

-0.0072

Neutral

(source)

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.0

Mutation Taster

=0/200

disease causing (ClinVar)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.000094

dbscSNV1_RF

Benign

0.24

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over