rs875989921

Positions:

• chr19-11113624-G-A
• chr19-11113624-G-T

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.1448G>A​(p.Trp483Ter) variant causes a stop gained change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,460,932 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 Pathogenic (★★). Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: LDLR NM_000527.5 stop_gained
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:10
• Conservation: PhyloP100: 9.88

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 19-11113624-G-A is Pathogenic according to our data. Variant chr19-11113624-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 226356.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-11113624-G-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
LDLR	NM_000527.5	c.1448G>A	p.Trp483Ter	stop_gained	10/18	ENST00000558518.6	NP_000518.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
LDLR	ENST00000558518.6	c.1448G>A	p.Trp483Ter	stop_gained	10/18	1	NM_000527.5	ENSP00000454071	P3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1460932 Hom.: 0 Cov.: 35 AF XY: 0.00000138 AC XY: 1 AN XY: 726848

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:10

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Hypercholesterolemia, familial, 1 Pathogenic:6

Pathogenic, no assertion criteria provided	research	Laboratorium voor Moleculaire Diagnostiek Experimentele Vasculaire Geneeskunde, Academisch Medisch Centrum	-	- -
Pathogenic, no assertion criteria provided	clinical testing	Cardiovascular Genetics Laboratory, PathWest Laboratory Medicine WA - Fiona Stanley Hospital	Sep 17, 2013	- -
Pathogenic, criteria provided, single submitter	research	Fundacion Hipercolesterolemia Familiar	Mar 01, 2016	- -
Pathogenic, criteria provided, single submitter	literature only	LDLR-LOVD, British Heart Foundation	Mar 25, 2016	- -
Pathogenic, criteria provided, single submitter	research	Brunham Lab, Centre for Heart and Lung Innovation, University of British Columbia	Mar 10, 2019	- -
Pathogenic, criteria provided, single submitter	clinical testing;in vitro	First Hospital of Lanzhou University, Lanzhou University	Feb 23, 2024	A 38-year-old female proband carried compound heterozygous variations(c.292G>A,c.1864G> A and c.1448G> A, according to the ACMG guidelines they were separately classified as Uncertain significance, Likely pathogenic and pathogenic).The proband presented with a xanthoma, corneal aneurysm, and coronary artery disease. The patient's serum cholesterol concentration remained greater than 13 mmol/L after receiving intensive statin, evolocumab and Inclisiran therapy.We speculate that the hepatocytes of the proband indicate the almostly absence of LDLR. The proband's mother, sister, and son all carried the c.292G>A,c.1864G> A variant. The proband's father, both brothers and daughter carried the c.1448G> A variant. All of her relatives showed hypercholesterolemia, but no atherosclerosis, xanthoma, or corneal aneurysm in the other relatives except the proband. Pedigree co-segregation evidence suggests that the three variants may be pathogenic variants in this familial hypercholesterolemic family. -

Familial hypercholesterolemia Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Jan 04, 2021	This variant changes 1 nucleotide in exon 10 of the LDLR gene, creating a premature translation stop signal. This variant is expected to result in an absent or non-functional protein product. This variant has been reported in over 25 individuals affected with familial hypercholesterolemia (PMID: 23375686, 25846081, 27170061, 28235710, 28502495, 29233637). 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. -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Apr 06, 2023	For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 226356). This premature translational stop signal has been observed in individual(s) with familial hypercholesterolemia (PMID: 7903864, 18247305). It has also been observed to segregate with disease in related individuals. This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Trp483*) 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). -

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Mar 08, 2024

Not observed at significant frequency in large population cohorts (gnomAD); Published functional studies demonstrate that this variant results in an altered whole LDLR life-cycle (PMID: 19073363); Nonsense 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; Also known as p.(W462*); This variant is associated with the following publications: (PMID: Zhou2017[article], 32793292, 27206935, 25907359, 27170061, 30876527, 30949068, 18247305, 27578104, 30415195, 10657581, 28235710, 29233637, 32759540, 28502495, 30108616, 23375686, 25846081, 30526649, 33994402, 31161821, 32629184, 30400955, 26608663, 25525159, 34037665, 34456049, 35979295, 36991406, Zhan2023[preprint], 38236436, 27206941, 38018368, 38297435, 19073363, 7903864, 33746137, 38003014) -

Cardiovascular phenotype Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

May 12, 2023

The c.1448G>A (p.W483*) alteration, located in exon 10 (coding exon 10) of the LDLR gene, consists of a G to A substitution at nucleotide position 1448. This changes the amino acid from a tryptophan (W) to a stop codon at amino acid position 483. This alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. This variant was not reported in population-based cohorts in the Genome Aggregation Database (gnomAD). This mutation, often reported in the Chinese population (also referred to as W462* or Trp462Stop), has been detected in the heterozygous, homozygous and compound heterozygous states in many individual with heterozygous or homozygous familial hypercholesterolemia (FH), and has shown segregation with FH in families (Sun, 1994; Schmidt, 2000; Cheng, 2008; Jiang, 2016; Marco-Benedí, 2022). Functional studies have shown this variant to adversely impact protein function (Cheng, 2008; Wang, 2009; Jiang, 2016). Based on the available evidence, this alteration is classified as pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.63	D
BayesDel_noAF	Pathogenic	0.58
CADD	Pathogenic	47
DANN	Uncertain	1.0
Eigen	Pathogenic	0.92
Eigen_PC	Pathogenic	0.78
FATHMM_MKL	Pathogenic	1.0	D
MutationTaster	Benign	1.0	A;A;A;A;A;A;A
Vest4		0.95
GERP RS		4.7
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: rs875989921; hg19: chr19-11224300;