NM_000527.5:c.2292delA

Variant names:

Variant summary

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

The NM_000527.5(LDLR):c.2292delA(p.Ile764MetfsTer2) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,830 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (★★). Variant results in nonsense mediated mRNA decay.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 6.8e-7 ( 0 hom. )

Consequence

LDLR
NM_000527.5 frameshift

Scores

Not classified

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:8

Conservation

PhyloP100: -0.646

Publications

2 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: 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 19-11123324-TA-T is Pathogenic according to our data. Variant chr19-11123324-TA-T is described in ClinVar as [Pathogenic]. Clinvar id is 226390.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 link	c.2292delA	p.Ile764MetfsTer2	frameshift_variant	Exon 15 of 18	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.2292delA	p.Ile764MetfsTer2	frameshift_variant	Exon 15 of 18	1	NM_000527.5	ENSP00000454071.1		P01130-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

6.84e-7

AC:

AN:

1461830

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

727212

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33480

American (AMR)

AF:

0.00

AC:

AN:

44720

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26136

East Asian (EAS)

AF:

0.00

AC:

AN:

39698

South Asian (SAS)

AF:

0.00

AC:

AN:

86258

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53396

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

8.99e-7

AC:

AN:

1111978

Other (OTH)

AF:

0.00

AC:

AN:

60396

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

GnomAD4 genome

Cov.:

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:8

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Hypercholesterolemia, familial, 1

Pathogenic:4

Mar 25, 2016

LDLR-LOVD, British Heart Foundation

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:literature only

- -

Jun 05, 2008

Cardiovascular Genetics Laboratory, PathWest Laboratory Medicine WA - Fiona Stanley Hospital

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Mar 01, 2016

Cardiovascular Research Group, Instituto Nacional de Saude Doutor Ricardo Jorge

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:curation;literature only

- -

Laboratorium voor Moleculaire Diagnostiek Experimentele Vasculaire Geneeskunde, Academisch Medisch Centrum

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:research

- -

Familial hypercholesterolemia

Pathogenic:2

Jun 04, 2025

GENinCode PLC

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.2292del p.(Ile764MetfsTer2) variant in LDLR is a frameshift variant predicted to create a premature stop codon leading to nonsense mediated decay in a gene in which loss-of-function is an established disease mechanism (PVS1). This variant has been reported in >10 FH patients meeting clinical criteria (PS4_STRONG; PMIDs 1352322, 16250003, 16389549, 17539906, 27680772, internal data) and was observed in the compound heterozygous state with a second pathogenic LDLR variant in an individual with a homozygous FH phenotype, where parental testing confirmed variants were in trans (PM3_MODERATE; PMID:1352322). The highest population minor allele frequency in gnomAD v4.1.0 is 0.0000008475 in European (non-Finnish) population, which is lower than the ClinGen FH VCEP threshold (<0.0002) so PM2_MODERATE is met. Based on the evidence listed above, we have classified this variant as Pathogenic. -

Feb 02, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This sequence change creates a premature translational stop signal (p.Ile764Metfs*2) in the LDLR gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in LDLR are known to be pathogenic (PMID: 20809525, 28645073). This variant is not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individual(s) with heterozygous or homozygous familial hypercholesterolemia (PMID: 1352322, 16159606, 16250003, 16389549, 22883975). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. Invitae Evidence Modeling of clinical and family history, age, sex, and reported ancestry of multiple individuals with this LDLR variant has been performed. This variant is expected to be pathogenic with a positive predictive value of at least 99%. This is a validated machine learning model that incorporates the clinical features of 363,995 individuals referred to our laboratory for LDLR testing. ClinVar contains an entry for this variant (Variation ID: 226390). For these reasons, this variant has been classified as Pathogenic. -

not provided

Pathogenic:1

Sep 09, 2024

GeneDx

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Frameshift variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss of function is a known mechanism of disease; Not observed at significant frequency in large population cohorts (gnomAD); Also known as I743Mfs*2, FH Tyrone; This variant is associated with the following publications: (PMID: 34037665, 16389549, 27680772, 10559517, 16250003, 22883975, 17539906, 1352322, 16159606, 37589137) -

Cardiovascular phenotype

Pathogenic:1

Oct 18, 2022

Ambry Genetics

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.2292delA pathogenic mutation, located in coding exon 15 of the LDLR gene, results from a deletion of one nucleotide at nucleotide position 2292, causing a translational frameshift with a predicted alternate stop codon (p.I764Mfs*2). This mutation (also referred to as p.I743Mfs*2, 2292delA or FH-Tyrone) co-occurred in trans with another LDLR mutation in an individual with homozygous familial hypercholesterolemia (HF), and has also been detected in several individuals with heterozygous FH (Webb JC et al. J Lipid Res, 1992 May;33:689-98; Graham CA et al. Atherosclerosis, 1999 Dec;147:309-16; Graham CA et al. Atherosclerosis, 2005 Oct;182:331-40; Fouchier SW et al. Hum Mutat, 2005 Dec;26:550-6; Taylor A et al. Clin Genet, 2007 Jun;71:561-8). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). In addition to the clinical data presented in the literature, this alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. As such, this alteration is interpreted as a disease-causing mutation. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

PhyloP100

-0.65

Mutation Taster

=0/200

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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NM_000527.5:c.2292delA

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over