chr19-11105279-C-T

Position:

• chr19-11105279-C-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.373C>T​(p.Gln125*) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,410 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: 33)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: LDLR NM_000527.5 stop_gained
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:4
• Conservation: PhyloP100: -0.206

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 19-11105279-C-T is Pathogenic according to our data. Variant chr19-11105279-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 251187.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-11105279-C-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
LDLR	NM_000527.5	c.373C>T	p.Gln125*	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.373C>T	p.Gln125*	stop_gained	4/18	1	NM_000527.5	ENSP00000454071.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461410 Hom.: 0 Cov.: 33 AF XY: 0.00000138 AC XY: 1 AN XY: 727026

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: 8.99e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

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	literature only	LDLR-LOVD, British Heart Foundation	Mar 25, 2016	- -
Pathogenic, criteria provided, single submitter	clinical testing	Genetics and Molecular Pathology, SA Pathology	Dec 19, 2022	The LDLR c.373C>T variant is classified as PATHOGENIC (PVS1, PM2, PS4_Supporting, PP4) The LDLR c.373C>T variant is a single nucleotide change in exon 4/18 which is predicted to result in premature termination of the protein product at codon 125. This variant is absent from population databases (PM2). This variant has been reported in the homozygous and heterozygous states in individuals with familial hypercholesterolemia (FH) (PS4_Supp). The clinical features of this case are highly specific for the LDLR gene and this patient has a well-defined syndrome with little overlap with other clinical presentations (PP4). This variant has been reported in dbSNP (rs875989899) and in the HGMD database: CM990792. It has been reported as Pathogenic by other diagnostic laboratories (ClinVar Variation ID: 251187). -

Homozygous familial hypercholesterolemia Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Oct 17, 2017

The p.Gln125X variant in LDLR has been reported in 3 individuals with clinical f eatures of familial hypercholesterolemia (FH), including one homozygous individu al with severe FH, segregated with disease in 3 affected relatives from 2 famili es (Bertolini 1999, Bertolini 2000, Bertolini 2013), and was absent from large p opulation studies. In vitro functional studies measuring LDL receptor activity i n cultured skin fibroblasts from the homozygous individual with severe FH show s everely impaired protein function, with less than 5% receptor residual activity (Bertolini 2013). This nonsense variant leads to a premature termination codon a t position 125, which is predicted to lead to a truncated or absent protein. Het erozygous loss of function of the LDLR gene is an established disease mechanism in FH. In summary, this variant meets criteria to be classified as pathogenic fo r familial hypercholesterolemia in an autosomal dominant manner based upon segre gation studies, absence from controls, predicted impact to the protein and funct ional evidence. -

Cardiovascular phenotype Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Jul 26, 2022

The p.Q125* pathogenic mutation (also known as c.373C>T), located in coding exon 4 of the LDLR gene, results from a C to T substitution at nucleotide position 373. This changes the amino acid from a glutamine to a stop codon within coding exon 4. This variant (also referred to as Q104*) has been reported in the homozygous and heterozygous states in individuals with familial hypercholesterolemia (FH), and was reported to result in significant reduction in receptor activity in assays on homozygous patient cells (Bertolini S et al. Arterioscler Thromb Vasc Biol, 1999 Feb;19:408-18; Vergotine J et al. S Afr Med J, 2001 Dec;91:1053-9; Suppressa P et al. J Clin Lipidol Jan;14:192-196). 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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.63	D
BayesDel_noAF	Uncertain	0.080
CADD	Uncertain	26
DANN	Uncertain	0.99
Eigen	Benign	-0.11
Eigen_PC	Benign	-0.47
FATHMM_MKL	Benign	0.63	D
Vest4		0.58
GERP RS		-0.91
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.2

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs875989899; hg19: chr19-11215955;