19-11105548-G-A

Position:

• chr19-11105548-G-A

Variant summary

Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PVS1 PM2 PP4

This summary comes from the ClinGen Evidence Repository: The NM_000527.5(LDLR):c.642G>A (p.Trp214Ter) variant is classified as Pathogenic for Familial Hypercholesterolemia by applying evidence codes (PVS1, PM2 and PP4) as defined by the ClinGen Familial Hypercholesterolemia Expert Panel LDLR-specific variant curation guidelines (https://doi.org/10.1016/j.gim.2021.09.012). The supporting evidence is as follows: PVS1 - variant is nonsense in exon 4 (amino terminal of amino acid 830), so PVS1 is met.PM2 - This variant is absent from gnomAD (gnomAD v2.1.1), so PM2 is met.PP4 - variant meets PM2 and was identified in at least 1 index case with SB criteria of definite FH (A+B) (Diagnostic criteria for heterozygous FH used in the paper were a TC>8.0 mmol/l and LDL- C>6.0 mmol/l if available, tendon xanthomata in the patient or in a first-degree relative, and a family history of hypercholesterolemia) from PMID 10532689 (Jensen et al., 1999), Denmark.so PP4 is met. LINK:https://erepo.genome.network/evrepo/ui/classification/CA10585029/MONDO:0007750/013

• Frequency: Genomes: not found (cov: 33)
• Consequence: LDLR NM_000527.5 stop_gained
• Clinical Significance: Pathogenic reviewed by expert panel P:4
• Conservation: PhyloP100: 7.89

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 11 ACMG points.

• PVS1: For more information check the summary or visit ClinGen Evidence Repository.
• PM2: For more information check the summary or visit ClinGen Evidence Repository.
• PP4: For more information check the summary or visit ClinGen Evidence Repository.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
LDLR	NM_000527.5	c.642G>A	p.Trp214*	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.642G>A	p.Trp214*	stop_gained	4/18	1	NM_000527.5	ENSP00000454071.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 33

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:4

Revision: reviewed by expert panel

Submissions by phenotype

Hypercholesterolemia, familial, 1 Pathogenic:2

Pathogenic, reviewed by expert panel	curation	ClinGen Familial Hypercholesterolemia Variant Curation Expert Panel	Dec 13, 2021	The NM_000527.5(LDLR):c.642G>A (p.Trp214Ter) variant is classified as Pathogenic for Familial Hypercholesterolemia by applying evidence codes (PVS1, PM2 and PP4) as defined by the ClinGen Familial Hypercholesterolemia Expert Panel LDLR-specific variant curation guidelines (https://doi.org/10.1016/j.gim.2021.09.012). The supporting evidence is as follows: PVS1 - variant is nonsense in exon 4 (amino terminal of amino acid 830), so PVS1 is met. PM2 - This variant is absent from gnomAD (gnomAD v2.1.1), so PM2 is met. PP4 - variant meets PM2 and was identified in at least 1 index case with SB criteria of definite FH (A+B) (Diagnostic criteria for heterozygous FH used in the paper were a TC>8.0 mmol/l and LDL- C>6.0 mmol/l if available, tendon xanthomata in the patient or in a first-degree relative, and a family history of hypercholesterolemia) from PMID 10532689 (Jensen et al., 1999), Denmark. so PP4 is met. -
Pathogenic, criteria provided, single submitter	literature only	LDLR-LOVD, British Heart Foundation	Mar 25, 2016	- -

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Quest Diagnostics Nichols Institute San Juan Capistrano

Dec 23, 2022

The LDLR c.642G>A (p.Trp214*) nonsense variant causes the premature termination of LDLR protein synthesis. The variant has not been reported in large, multi-ethnic general populations (http://gnomad.broadinstitute.org). In the published literature, the variant has been reported in individuals with familial hypercholesterolemia (PMIDs: 16542394 (2006), 10532689 (1999)). Based on the available information, this variant is classified as pathogenic. -

Cardiovascular phenotype Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Jan 16, 2018

The p.W214* pathogenic mutation (also known as c.642G>A), located in coding exon 4 of the LDLR gene, results from a G to A substitution at nucleotide position 642. This changes the amino acid from a tryptophan to a stop codon within coding exon 4. This alteration has been reported in a familial hypercholesterolemia cohort (Jensen HK et al. Atherosclerosis. 1999 Oct;146:337-44 (reported as W193X)). 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
BayesDel_addAF	Pathogenic	0.63	D
BayesDel_noAF	Pathogenic	0.63
CADD	Pathogenic	37
DANN	Uncertain	1.0
Eigen	Pathogenic	0.83
Eigen_PC	Pathogenic	0.68
FATHMM_MKL	Pathogenic	0.99	D
Vest4		0.84
GERP RS		5.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7

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: rs879254606; hg19: chr19-11216224;