19-11123216-GGCTAAAGGTCA-G

Position:

• chr19-11123216-GGCTAAAGGTCA-G

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.2187_2197delAAAGGTCAGCT​(p.Lys730fs) 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 1,461,828 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: 30)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: LDLR NM_000527.5 frameshift
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:4
• Conservation: PhyloP100: 0.349

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 19-11123216-GGCTAAAGGTCA-G is Pathogenic according to our data. Variant chr19-11123216-GGCTAAAGGTCA-G is described in ClinVar as [Pathogenic]. Clinvar id is 252251.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-11123216-GGCTAAAGGTCA-G is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
LDLR	NM_000527.5	c.2187_2197delAAAGGTCAGCT	p.Lys730fs	frameshift_variant	15/18	ENST00000558518.6	NP_000518.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
LDLR	ENST00000558518.6	c.2187_2197delAAAGGTCAGCT	p.Lys730fs	frameshift_variant	15/18	1	NM_000527.5	ENSP00000454071.1

Frequencies

GnomAD3 genomes Cov.: 30

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461828 Hom.: 0 AF XY: 0.00000138 AC XY: 1 AN XY: 727204

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

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.: 30

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Hypercholesterolemia, familial, 1 Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	U4M - Lille University & CHRU Lille, Université de Lille - CHRU de Lille	Mar 30, 2017	- -
Pathogenic, criteria provided, single submitter	literature only	LDLR-LOVD, British Heart Foundation	Mar 25, 2016	- -

Cardiovascular phenotype Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Dec 08, 2022

The c.2187_2197del11 pathogenic mutation, located in coding exon 15 of the LDLR gene, results from a deletion of 11 nucleotides at nucleotide positions 2187 to 2197, causing a translational frameshift with a predicted alternate stop codon (p.K730Hfs*48). This variant has been detected in familial hypercholesterolemia cohorts (Marduel M et al. Hum Mutat, 2010 Nov;31:E1811-24; Futema M et al. Atherosclerosis, 2013 Jul;229:161-8). 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. -

Familial hypercholesterolemia Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 12, 2017

For these reasons, this variant has been classified as Pathogenic. Loss-of-function variants in LDLR are known to be pathogenic (PMID: 20809525). This particular variant has been reported in the literature in two families affected with hypercholesterolemia (PMID: 20809525, 23669246). This variant is also known in the literature as p.Leu729Leufs*39. This sequence change deletes 11 nucleotides from exon 15 of the LDLR mRNA (c.2187_2197del), causing a frameshift at codon 730. This creates a premature translational stop signal (p.Lys730Hisfs*48) and is expected to result in an absent or disrupted protein product. -

Computational scores

Source: dbNSFP v4.3

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs879255159; hg19: chr19-11233892;