rs752191968

Variant names:

• chr19-11105242-C-CG
• rs752191968
• NM_000527.5:c.337dupG

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1 PM2 PP5_Very_Strong

The NM_000527.5(LDLR):​c.337dupG​(p.Glu113GlyfsTer17) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,461,198 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: 33)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: LDLR NM_000527.5 frameshift
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:5
• Conservation: PhyloP100: 2.65

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]

ACMG classification

Verdict is Pathogenic. Variant got 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 19-11105242-C-CG is Pathogenic according to our data. Variant chr19-11105242-C-CG is described in ClinVar as [Pathogenic]. Clinvar id is 440560.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.337dupG	p.Glu113GlyfsTer17	frameshift_variant	Exon 4 of 18	ENST00000558518.6	NP_000518.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
LDLR	ENST00000558518.6	c.337dupG	p.Glu113GlyfsTer17	frameshift_variant	Exon 4 of 18	1	NM_000527.5	ENSP00000454071.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD3 exomes AF: 0.00000399 AC: 1 AN: 250566 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 135724

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000289

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1461198 Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0 AN XY: 726934

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000224

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome Cov.: 33

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Hypercholesterolemia Pathogenic:1

Sep 25, 2019

UCSF Pediatric Lipid Clinic, University of California, San Francisco

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.E113fs variant segregates with elevated level of LDL-C in a family of 5 individuals. The allele frequency of this variant in the population is 0.00001 as reported by the ExAC database. -

Hypercholesterolemia, familial, 1 Pathogenic:1

-

Laboratorium voor Moleculaire Diagnostiek Experimentele Vasculaire Geneeskunde, Academisch Medisch Centrum

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: research

- -

not provided Pathogenic:1

Jul 20, 2017

Stanford Center for Inherited Cardiovascular Disease, Stanford University

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: provider interpretation

p.Glu113Glyfs*17 (c.337dupG; also known as 338insG) in exon 4 of the LDLR gene (NM_000527.4) Given that this is a loss-of-function variant in a gene in which truncation is a known mechanism of disease, moderate case data and its rarity in the general population, we consider this variant disease-causing and we do feel it is suitable for assessing risk in healthy relatives ("predictive genetic testing"). This variant causes a shift in the reading frame of the LDLR gene, producing a truncated protein. Loss-of-function (truncated proteins) variants are a known mechanism of LDLR-associated familial hypercholesterolemia. The variant has been seen in at least 4 unrelated cases of familial hypercholesterolemia (not including this patient's family). There is moderate case data. This variant was present in 4 of 46 unrelated patients with familial hypercholesterolemia (Robles-Osorio et al, 2006), and was a "common" variant identified amongst 123 unrelated Mexican patients (per an abstract by Vazques Cardenas et al, 2015). This variant is not present in ClinVar; however another truncating variant at this codon (c.337G>T; p.Glu113Ter) is classified as pathogenic by four laboratories. The variant was reported online in 1 of 122,762 individuals in the Genome Aggregation Consortium Dataset (gnomAD; http://gnomad.broadinstitute.org/), which currently includes variant calls on >140,000 unrelated individuals of African, Asian, European, Ashkenazi, Latino descent. Specifically, the variant was observed in 1 of 16,789 individuals of Latino descent (MAF=0.003%). The phenotype of those individuals is not publicly available. The dataset is comprised of multiple cohorts, some of which were recruited from the general population, others were enriched for common cardiovascular disease. Note that other variants with strong evidence for pathogenicity have been seen at similar frequencies in datasets like this so this does not necessarily rule out pathogenicity (Pan et al 2012). -

Cardiovascular phenotype Pathogenic:1

Jul 13, 2020

Ambry Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.337dupG pathogenic mutation, located in coding exon 4 of the LDLR gene, results from a duplication of G at nucleotide position 337, causing a translational frameshift with a predicted alternate stop codon (p.E113Gfs*17). This alteration (referred to as 338insG) has been detected in a cohort of individuals reported to have familial hypercholesterolemia (Robles-Osorio L et al. Arch. Med. Res., 2006 Jan;37:102-8). This alteration was also detected in a Mexican family with familial hypercholesterolemia. In this family, two homozygous children were reported, and both had higher LDL-C and total cholesterol levels than their heterozygous parents and sibling (Wong KHY et al. Mol Genet Genomic Med, 2019 12;7:e1007). 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

Jan 27, 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.Glu113Glyfs*17) 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 present in population databases (rs752191968, gnomAD 0.003%). This premature translational stop signal has been observed in individuals with familial hypercholesterolemia (PMID: 16314194). 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. This variant is also known as 338insG. ClinVar contains an entry for this variant (Variation ID: 440560). For these reasons, this variant has been classified as Pathogenic. -

Computational scores

Source: dbNSFP v4.3

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs752191968; hg19: chr19-11215918;