NM_000527.5:c.933delA

Variant names:

• chr19-11107504-CA-C
• rs879254723
• NM_000527.5:c.933delA

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.933delA​(p.Glu312SerfsTer58) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000206 in 1,456,276 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: 0.0000021 (0 hom.)
• Consequence: LDLR NM_000527.5 frameshift
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:5
• Conservation: PhyloP100: 3.48
• 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 19-11107504-CA-C is Pathogenic according to our data. Variant chr19-11107504-CA-C is described in ClinVar as Pathogenic. ClinVar VariationId is 251533.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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LDLR	NM_000527.5	MANE Select	c.933delA	p.Glu312SerfsTer58	frameshift	Exon 6 of 18	NP_000518.1
	LDLR	NM_001195798.2		c.933delA	p.Glu312SerfsTer58	frameshift	Exon 6 of 18	NP_001182727.1
	LDLR	NM_001195799.2		c.810delA	p.Glu271SerfsTer58	frameshift	Exon 5 of 17	NP_001182728.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LDLR	ENST00000558518.6	TSL:1 MANE Select	c.933delA	p.Glu312SerfsTer58	frameshift	Exon 6 of 18	ENSP00000454071.1
	LDLR	ENST00000252444.10	TSL:1	c.1191delA	p.Glu398SerfsTer58	frameshift	Exon 6 of 18	ENSP00000252444.6
	LDLR	ENST00000558013.5	TSL:1	c.933delA	p.Glu312SerfsTer58	frameshift	Exon 6 of 18	ENSP00000453346.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000206 AC: 3 AN: 1456276 Hom.: 0 Cov.: 32 AF XY: 0.00000138 AC XY: 1 AN XY: 724434

African (AFR) AF: 0.00 AC: 0 AN: 33284

American (AMR) AF: 0.00 AC: 0 AN: 44538

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25928

East Asian (EAS) AF: 0.00 AC: 0 AN: 39410

South Asian (SAS) AF: 0.00 AC: 0 AN: 86144

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52836

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5748

European-Non Finnish (NFE) AF: 0.00000180 AC: 2 AN: 1108406

Other (OTH) AF: 0.0000167 AC: 1 AN: 59982

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Hypercholesterolemia, familial, 1 Pathogenic:2

Jun 26, 2023

All of Us Research Program, National Institutes of Health

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant deletes 1 nucleotide in exon 6 in the type A repeat 7 of the LDLR gene, creating a frameshift and premature translation stop signal. This variant is expected to result in an absent or non-functional protein product. This variant has been reported in an individual affected with familial hypercholesterolemia (PMID: 16389549) and in multiple individuals affected with possible familial hypercholesterolemia (PMID: 10559517, 27680772, 34037665). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Loss of LDLR function is a known mechanism of disease (clinicalgenome.org). Based on the available evidence, this variant is classified as Pathogenic.

Mar 25, 2016

LDLR-LOVD, British Heart Foundation

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: literature only

not provided Pathogenic:1

Feb 21, 2025

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; Identified in patients with familial hypercholesterolemia (FH) referred for genetic testing at GeneDx and in published literature (PMID: 10559517, 16389549, 33740630); Not observed at significant frequency in large population cohorts (gnomAD); Also known as c.932delA; This variant is associated with the following publications: (PMID: 21310417, 18700895, 16389549, 34040191, 34037665, 37589137, 16159606, 27680772, 10559517, 33740630)

Cardiovascular phenotype Pathogenic:1

Oct 21, 2023

Ambry Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.933delA pathogenic mutation, located in coding exon 6 of the LDLR gene, results from a deletion of one nucleotide at nucleotide position 933, causing a translational frameshift with a predicted alternate stop codon (p.E312Sfs*58). This mutation (also referred to as 932delA) has been detected in a number of individuals with familial hypercholesterolemia (Ajufo E et al. Genet Med, 2021 Sep;23:1697-1704; Graham CA et al. Atherosclerosis, 2005 Oct;182:331-40). 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.

Familial hypercholesterolemia Pathogenic:1

May 28, 2022

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 251533). This variant is also known as 932delA. This premature translational stop signal has been observed in individuals with familial hypercholesterolemia (FH) (PMID: 10559517, 16389549). This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Glu312Serfs*58) 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).

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		3.5
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: rs879254723; hg19: chr19-11218180;