19-11105470-C-G

Position:

• chr19-11105470-C-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.564C>G​(p.Tyr188*) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000205 in 1,461,716 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: LDLR NM_000527.5 stop_gained
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:11
• Conservation: PhyloP100: -0.109

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 19-11105470-C-G is Pathogenic according to our data. Variant chr19-11105470-C-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 3727.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-11105470-C-G is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
LDLR	NM_000527.5	c.564C>G	p.Tyr188*	stop_gained	4/18	ENST00000558518.6	NP_000518.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
LDLR	ENST00000558518.6	c.564C>G	p.Tyr188*	stop_gained	4/18	1	NM_000527.5	ENSP00000454071.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000205 AC: 3 AN: 1461716 Hom.: 0 Cov.: 33 AF XY: 0.00000138 AC XY: 1 AN XY: 727170

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: 0.00000180

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome Cov.: 33

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.00 AC: 0

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:11

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Hypercholesterolemia, familial, 1 Pathogenic:7

Pathogenic, no assertion criteria provided	research	Laboratorium voor Moleculaire Diagnostiek Experimentele Vasculaire Geneeskunde, Academisch Medisch Centrum	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Centre de Génétique Moléculaire et Chromosomique, Unité de génétique de l'Obésité et des Dyslipidémies, APHP, GH Hôpitaux Universitaires Pitié-Salpêtrière / Charles-Foix	Dec 16, 2016	subject mutated among 2600 FH index cases screened = 1/previously described in association with FH -
Pathogenic, no assertion criteria provided	research	Rajaie Cardiovascular, Medical and Research Center, Iran University of Medical Sciences	-	- -
Pathogenic, no assertion criteria provided	literature only	OMIM	Feb 01, 1992	- -
Pathogenic, criteria provided, single submitter	curation;literature only	Cardiovascular Research Group, Instituto Nacional de Saude Doutor Ricardo Jorge	Mar 01, 2016	- -
Pathogenic, criteria provided, single submitter	literature only	LDLR-LOVD, British Heart Foundation	Mar 25, 2016	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Robarts Research Institute, Western University	-	- -

Familial hypercholesterolemia Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Nov 22, 2022	This sequence change creates a premature translational stop signal (p.Tyr188*) 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). For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 3727). This variant is also known as p.Tyr167*. This premature translational stop signal has been observed in individuals with familial hypercholesterolemia (PMID: 1734722, 8882879). It has also been observed to segregate with disease in related individuals. -
Pathogenic, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Nov 21, 2018	This variant (also known as Y167X and as FH Druze) changes 1 nucleotide in exon 4 of the LDLR gene, creating a premature translation stop signal. This variant has been reported in multiple individuals affected with familial hypercholesterolemia (PMID: 1734722, 8882879, 17142622) and shown to segregate with disease in 6 individuals in a family of Druze origin (PMID: 1734722). An experimental study has shown that no LDLR protein was detectable in cells obtained from an individual homozygous for this variant (PMID: 1734722). 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. Based on available evidence, this variant is classified as Pathogenic. -

Homozygous familial hypercholesterolemia Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Mar 06, 2019

The p.Tyr188X variant in LDLR has been reported in 1 homozygous individual with severe hypercholesterolemia, 2 heterozygous individuals with hypercholesterolemia, and segregated with disease in 5 affected individuals from 1 family (Landsberger 1992. Humphries 2006). It was absent from large population studies, but is reported in ClinVar (Variation ID: 3727). This nonsense variant leads to a premature termination codon at position 188, which is predicted to lead to a truncated or absent protein. Loss of function of the LDLR gene is an established disease mechanism in autosomal dominant hypercholesterolemia. In vitro functional studies support an impact on protein function (Landsberger 1996). In summary, this variant meets criteria to be classified as pathogenic for autosomal dominant hypercholesterolemia. ACMG/AMP Criteria applied: PVS1, PM2, PM3, PP1_Moderate, PS3_Supporting, PS4_Supporting. -

Cardiovascular phenotype Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Sep 30, 2021

The p.Y188* pathogenic mutation (also known as c.564C>G), located in coding exon 4 of the LDLR gene, results from a C to G substitution at nucleotide position 564. This changes the amino acid from a tyrosine to a stop codon within coding exon 4. This mutation (also referred to as Y167*, Stop 167, and FH-Druze) has been detected in several individuals with familial hypercholesterolemia and segregated with disease in a family (Landsberger D et al. Am J Hum Genet, 1992 Feb;50:427-33; Humphries SE et al. J Med Genet, 2006 Dec;43:943-9; Dron JS et al. BMC Med Genomics, 2020 02;13:23). In studies of patient cells with this variant, LDL binding and degradation as well as LDL receptor synthesis and processing were significantly reduced or absent compared to controls (Landsberger D et al. Am J Hum Genet, 1992 Feb;50:427-33). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). 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
BayesDel_addAF	Pathogenic	0.63	D
BayesDel_noAF	Benign	-0.29
CADD	Uncertain	24
DANN	Benign	0.91
Eigen	Benign	-0.57
Eigen_PC	Benign	-0.92
FATHMM_MKL	Benign	0.73	D
Vest4		0.61
GERP RS		0.14

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

LitVar

Other links and lift over

dbSNP: rs121908034; hg19: chr19-11216146;