NM_000527.5:c.2068dupC

Variant names:

• chr19-11120445-A-AC
• rs879255130
• NM_000527.5:c.2068dupC

Variant summary

Our verdict is Pathogenic. The variant received 18 ACMG points: 18P and 0B. PVS1 PM2 PP5_Very_Strong

The NM_000527.5(LDLR):​c.2068dupC​(p.His690ProfsTer27) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic (★★). Synonymous variant affecting the same amino acid position (i.e. H690H) has been classified as Likely benign. Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 32)
• Consequence: LDLR NM_000527.5 frameshift
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:2
• Conservation: PhyloP100: 0.0190
• Publications: 2 publications found

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

ACMG classification

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 19-11120445-A-AC is Pathogenic according to our data. Variant chr19-11120445-A-AC is described in CliVar as Pathogenic. Clinvar id is 375830.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-11120445-A-AC is described in CliVar as Pathogenic. Clinvar id is 375830.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-11120445-A-AC is described in CliVar as Pathogenic. Clinvar id is 375830.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-11120445-A-AC is described in CliVar as Pathogenic. Clinvar id is 375830.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-11120445-A-AC is described in CliVar as Pathogenic. Clinvar id is 375830.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-11120445-A-AC is described in CliVar as Pathogenic. Clinvar id is 375830.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-11120445-A-AC is described in CliVar as Pathogenic. Clinvar id is 375830.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-11120445-A-AC is described in CliVar as Pathogenic. Clinvar id is 375830.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-11120445-A-AC is described in CliVar as Pathogenic. Clinvar id is 375830.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-11120445-A-AC is described in CliVar as Pathogenic. Clinvar id is 375830.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-11120445-A-AC is described in CliVar as Pathogenic. Clinvar id is 375830.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-11120445-A-AC is described in CliVar as Pathogenic. Clinvar id is 375830.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-11120445-A-AC is described in CliVar as Pathogenic. Clinvar id is 375830.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-11120445-A-AC is described in CliVar as Pathogenic. Clinvar id is 375830.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-11120445-A-AC is described in CliVar as Pathogenic. Clinvar id is 375830.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-11120445-A-AC is described in CliVar as Pathogenic. Clinvar id is 375830.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-11120445-A-AC is described in CliVar as Pathogenic. Clinvar id is 375830.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-11120445-A-AC is described in CliVar as Pathogenic. Clinvar id is 375830.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-11120445-A-AC is described in CliVar as Pathogenic. Clinvar id is 375830.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-11120445-A-AC is described in CliVar as Pathogenic. Clinvar id is 375830.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-11120445-A-AC is described in CliVar as Pathogenic. Clinvar id is 375830.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-11120445-A-AC is described in CliVar as Pathogenic. Clinvar id is 375830.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-11120445-A-AC is described in CliVar as Pathogenic. Clinvar id is 375830.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-11120445-A-AC is described in CliVar as Pathogenic. Clinvar id is 375830.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-11120445-A-AC is described in CliVar as Pathogenic. Clinvar id is 375830.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-11120445-A-AC is described in CliVar as Pathogenic. Clinvar id is 375830.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
LDLR	NM_000527.5	c.2068dupC	p.His690ProfsTer27	frameshift_variant	Exon 14 of 18	ENST00000558518.6	NP_000518.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
LDLR	ENST00000558518.6	c.2068dupC	p.His690ProfsTer27	frameshift_variant	Exon 14 of 18	1	NM_000527.5	ENSP00000454071.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 35

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Hypercholesterolemia, familial, 1 Pathogenic:2

Mar 01, 2016

Laboratory of Genetics and Molecular Cardiology, University of São Paulo

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: research

- -

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: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

subject mutated among 2600 FH index cases screened = 1 -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
PhyloP100		0.019
Mutation Taster		=0/200	disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs879255130; hg19: chr19-11231121;