NM_000527.5:c.190+58C>T

Variant names:

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_StrongBP6_ModerateBA1

The NM_000527.5(LDLR):c.190+58C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00766 in 1,541,000 control chromosomes in the GnomAD database, including 627 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

Frequency

Genomes: 𝑓 0.013 ( 67 hom., cov: 33)

Exomes 𝑓: 0.0071 ( 560 hom. )

Consequence

LDLR
NM_000527.5 intron

Scores

Clinical Significance

Likely benign criteria provided, single submitter B:1

Conservation

PhyloP100: -0.916

Publications

4 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: Benign. The variant received -14 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.82).

BP6

Variant 19-11100403-C-T is Benign according to our data. Variant chr19-11100403-C-T is described in CliVar as Likely_benign. Clinvar id is 1712176.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr19-11100403-C-T is described in CliVar as Likely_benign. Clinvar id is 1712176.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr19-11100403-C-T is described in CliVar as Likely_benign. Clinvar id is 1712176.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr19-11100403-C-T is described in CliVar as Likely_benign. Clinvar id is 1712176.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr19-11100403-C-T is described in CliVar as Likely_benign. Clinvar id is 1712176.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr19-11100403-C-T is described in CliVar as Likely_benign. Clinvar id is 1712176.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr19-11100403-C-T is described in CliVar as Likely_benign. Clinvar id is 1712176.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr19-11100403-C-T is described in CliVar as Likely_benign. Clinvar id is 1712176.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr19-11100403-C-T is described in CliVar as Likely_benign. Clinvar id is 1712176.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr19-11100403-C-T is described in CliVar as Likely_benign. Clinvar id is 1712176.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr19-11100403-C-T is described in CliVar as Likely_benign. Clinvar id is 1712176.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr19-11100403-C-T is described in CliVar as Likely_benign. Clinvar id is 1712176.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr19-11100403-C-T is described in CliVar as Likely_benign. Clinvar id is 1712176.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr19-11100403-C-T is described in CliVar as Likely_benign. Clinvar id is 1712176.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr19-11100403-C-T is described in CliVar as Likely_benign. Clinvar id is 1712176.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr19-11100403-C-T is described in CliVar as Likely_benign. Clinvar id is 1712176.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr19-11100403-C-T is described in CliVar as Likely_benign. Clinvar id is 1712176.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr19-11100403-C-T is described in CliVar as Likely_benign. Clinvar id is 1712176.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr19-11100403-C-T is described in CliVar as Likely_benign. Clinvar id is 1712176.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr19-11100403-C-T is described in CliVar as Likely_benign. Clinvar id is 1712176.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr19-11100403-C-T is described in CliVar as Likely_benign. Clinvar id is 1712176.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr19-11100403-C-T is described in CliVar as Likely_benign. Clinvar id is 1712176.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr19-11100403-C-T is described in CliVar as Likely_benign. Clinvar id is 1712176.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr19-11100403-C-T is described in CliVar as Likely_benign. Clinvar id is 1712176.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr19-11100403-C-T is described in CliVar as Likely_benign. Clinvar id is 1712176.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr19-11100403-C-T is described in CliVar as Likely_benign. Clinvar id is 1712176.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr19-11100403-C-T is described in CliVar as Likely_benign. Clinvar id is 1712176.Status of the report is criteria_provided_single_submitter, 1 stars.

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.137 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
LDLR	NM_000527.5 link	c.190+58C>T		intron_variant	Intron 2 of 17	ENST00000558518.6	NP_000518.1	P01130-1A0A024R7D5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
LDLR	ENST00000558518.6 link	c.190+58C>T		intron_variant	Intron 2 of 17	1	NM_000527.5	ENSP00000454071.1		P01130-1

Frequencies

GnomAD3 genomes

AF:

0.0131

AC:

1991

AN:

152176

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0195

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0178

Gnomad ASJ

AF:

0.0112

Gnomad EAS

AF:

0.145

Gnomad SAS

AF:

0.00663

Gnomad FIN

AF:

0.000847

Gnomad MID

AF:

0.00316

Gnomad NFE

AF:

0.000779

Gnomad OTH

AF:

0.0115

GnomAD4 exome

AF:

0.00707

AC:

9820

AN:

1388706

Hom.:

560

Cov.:

AF XY:

0.00686

AC XY:

4760

AN XY:

693824

show subpopulations

African (AFR)

AF:

0.0221

AC:

708

AN:

32022

American (AMR)

AF:

0.0244

AC:

1051

AN:

43086

Ashkenazi Jewish (ASJ)

AF:

0.00926

AC:

236

AN:

25494

East Asian (EAS)

AF:

0.159

AC:

6203

AN:

39044

South Asian (SAS)

AF:

0.00479

AC:

402

AN:

83924

European-Finnish (FIN)

AF:

0.00145

AC:

AN:

44820

Middle Eastern (MID)

AF:

0.00264

AC:

AN:

5302

European-Non Finnish (NFE)

AF:

0.000572

AC:

605

AN:

1056924

Other (OTH)

AF:

0.00923

AC:

536

AN:

58090

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.499

Heterozygous variant carriers

494

989

1483

1978

2472

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

138

276

414

552

690

<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:

0.0130

AC:

1987

AN:

152294

Hom.:

Cov.:

AF XY:

0.0142

AC XY:

1054

AN XY:

74474

show subpopulations

African (AFR)

AF:

0.0194

AC:

806

AN:

41566

American (AMR)

AF:

0.0177

AC:

271

AN:

15278

Ashkenazi Jewish (ASJ)

AF:

0.0112

AC:

AN:

3472

East Asian (EAS)

AF:

0.145

AC:

753

AN:

5176

South Asian (SAS)

AF:

0.00642

AC:

AN:

4826

European-Finnish (FIN)

AF:

0.000847

AC:

AN:

10624

Middle Eastern (MID)

AF:

0.00340

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000779

AC:

AN:

68032

Other (OTH)

AF:

0.0114

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.494

Heterozygous variant carriers

198

298

397

496

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

120

<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:

0.00487

Hom.:

Bravo

AF:

0.0153

Asia WGS

AF:

0.0610

AC:

213

AN:

3478

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not provided

Benign:1

Apr 24, 2022

GeneDx

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.82

CADD

Benign

0.87

(source)

DANN

Benign

0.60

PhyloP100

-0.92

Mutation Taster

=100/0

polymorphism

(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

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over