rs760436036

Positions:

• chr19-11120419-T-A
• chr19-11120419-T-C

Variant summary

Our verdict is Pathogenic. Variant got 19 ACMG points: 19P and 0B. PVS1 PM2 PP3 PP5_Very_Strong

The NM_000527.5(LDLR):​c.2037T>A​(p.Tyr679Ter) 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 1,461,850 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: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: LDLR NM_000527.5 stop_gained
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:6
• Conservation: PhyloP100: 0.506

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 19 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
• PP3: Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.
• PP5: Variant 19-11120419-T-A is Pathogenic according to our data. Variant chr19-11120419-T-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 252183.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-11120419-T-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
LDLR	NM_000527.5	c.2037T>A	p.Tyr679Ter	stop_gained	14/18	ENST00000558518.6	NP_000518.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
LDLR	ENST00000558518.6	c.2037T>A	p.Tyr679Ter	stop_gained	14/18	1	NM_000527.5	ENSP00000454071	P3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461850 Hom.: 0 Cov.: 35 AF XY: 0.00000138 AC XY: 1 AN XY: 727232

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.: 32

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:6

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	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	- -

Homozygous familial hypercholesterolemia Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Oct 11, 2019

The p.Tyr679X variant in LDLR has been reported in 1 individual with hypercholesterolemia (Taylor 2007). It was absent from large population studies. This nonsense variant leads to a premature termination codon at position 679, 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 familial hypercholesterolemia. In summary, although additional studies are required to fully establish its clinical significance, this variant meets criteria to be classified as likely pathogenic for autosomal dominant familial hypercholesterolemia. ACMG/AMP Criteria applied: PVS1, PM2. -

not provided Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Jun 30, 2022

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; Not observed at significant frequency in large population cohorts (gnomAD); Observed in an individual with possible familial hypercholesterolemia (Taylor et al., 2007); This variant is associated with the following publications: (PMID: 25525159, 33087929, 17539906) -

Cardiovascular phenotype Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Nov 21, 2020

The p.Y679* pathogenic mutation (also known as c.2037T>A), located in coding exon 14 of the LDLR gene, results from a T to A substitution at nucleotide position 2037. This changes the amino acid from a tyrosine to a stop codon within coding exon 14. This mutation has been reported in a familial hypercholesterolemia cohort, although clinical details were limited (Taylor A et al. Clin Genet, 2007 Jun;71:561-8). 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

Likely pathogenic, criteria provided, single submitter

curation

Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard

Jan 22, 2020

The p.Tyr679Ter variant in LDLR has been reported in one individual from the UK with familial hypercholesterolemia (PMID: 17539906), and was absent from large population studies. This variant has also been reported in ClinVar as pathogenic (Variation ID: 252183). This nonsense variant leads to a premature termination codon at position 679, which is predicted to lead to a truncated or absent protein. Heterozygous loss of function of the LDLR gene is an established disease mechanism in familial hypercholesterolemia. In summary, although additional studies are required to fully establish its clinical significance, this variant is likely pathogenic. ACMG/AMP Criteria applied: PVS1, PM2 (Richards 2015). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.63	D
BayesDel_noAF	Pathogenic	0.59
CADD	Pathogenic	41
DANN	Uncertain	0.99
Eigen	Uncertain	0.33
Eigen_PC	Benign	0.14
FATHMM_MKL	Uncertain	0.97	D
MutationTaster	Benign	1.0	A;A;A;A;A;A;D
Vest4		0.95
GERP RS		2.9
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.63		Details are displayed if max score is > 0.2
DS_AG_spliceai		0.63		Position offset: 22

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

Publications

LitVar

Other links and lift over

dbSNP: rs760436036; hg19: chr19-11231095;