19-11120383-T-G

Variant names:

• chr19-11120383-T-G
• rs879255109
• NM_000527.5:c.2001T>G

Variant summary

Our verdict is Pathogenic. The variant received 19 ACMG points: 19P and 0B. PM1 PM2 PM5 PP2 PP3_Strong PP5_Very_Strong

The NM_000527.5(LDLR):​c.2001T>G​(p.Cys667Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. C667Y) has been classified as Likely pathogenic.

• Frequency: Genomes: not found (cov: 32)
• Consequence: LDLR NM_000527.5 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:4
• Conservation: PhyloP100: 1.17
• Publications: 3 publications found

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]

LDLR Gene-Disease associations (from GenCC):

• hypercholesterolemia, familial, 1

  Inheritance: AD, SD Classification: DEFINITIVE, STRONG Submitted by: Genomics England PanelApp, Labcorp Genetics (formerly Invitae), Laboratory for Molecular Medicine, ClinGen
• homozygous familial hypercholesterolemia

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Pathogenic. The variant received 19 ACMG points.

• PM1: In a hotspot region, there are 11 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 15 uncertain in NM_000527.5
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr19-11120382-G-A is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 3689.Status of the report is reviewed_by_expert_panel, 3 stars.
• PP2: Missense variant in the gene, where a lot of missense mutations are associated with disease in ClinVar. The gene has 678 curated pathogenic missense variants (we use a threshold of 10). The gene has 92 curated benign missense variants. Gene score misZ: 0.12407 (below the threshold of 3.09). Trascript score misZ: 0.59338 (below the threshold of 3.09). GenCC associations: The gene is linked to hypercholesterolemia, familial, 1, homozygous familial hypercholesterolemia.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.995
• PP5: Variant 19-11120383-T-G is Pathogenic according to our data. Variant chr19-11120383-T-G is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 252168.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
LDLR	NM_000527.5	c.2001T>G	p.Cys667Trp	missense_variant	Exon 14 of 18	ENST00000558518.6	NP_000518.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
LDLR	ENST00000558518.6	c.2001T>G	p.Cys667Trp	missense_variant	Exon 14 of 18	1	NM_000527.5	ENSP00000454071.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 35

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Hypercholesterolemia, familial, 1 Pathogenic:3

Nov 21, 2019

Institute of Human Genetics, University of Leipzig Medical Center

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was identified as homozygous

Mar 30, 2017

U4M - Lille University & CHRU Lille, Université de Lille - CHRU de Lille

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Mar 25, 2016

LDLR-LOVD, British Heart Foundation

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: literature only

LDLR-related disorder Pathogenic:1

Jun 16, 2023

PreventionGenetics, part of Exact Sciences

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The LDLR c.2001T>G variant is predicted to result in the amino acid substitution p.Cys667Trp. This variant, also known as Cys646Trp using legacy nomenclature, was reported in an individual with hypercholesterolemia (Patient C4 in Nissen et al 1998. PubMed ID: 9727746). This variant has not been reported in a large population database (http://gnomad.broadinstitute.org), indicating this variant is rare. Of note, several other missense variant impacting the same amino acid (p.Cys667Ser, p.Cys667Arg, p.Cys667Tyr and p.Cys667Phe) have been reported in patients with hypercholesterolemia (Zakharova et al. 2005. PubMed ID: 15701167; Vergopoulos et al. 1997. PubMed ID: 9412789; Leitersdorf. 1990. PubMed ID: 2318961; Heath et al. 2001. PubMed ID: 11313767). Based on this evidence, we interpret the c.2001T>G (p.Cys667Trp) variant as pathogenic.

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Pathogenic	0.54	D
BayesDel_noAF	Pathogenic	0.54
CADD	Uncertain	24
DANN	Uncertain	0.99
DEOGEN2	Pathogenic	0.96	D;.;.;.;.
Eigen	Pathogenic	0.68
Eigen_PC	Uncertain	0.53
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Benign	0.83	T;T;T;T;T
M_CAP	Pathogenic	0.97	D
MetaRNN	Pathogenic	0.99	D;D;D;D;D
MetaSVM	Pathogenic	1.0	D
MutationAssessor	Pathogenic	4.5	H;.;.;.;H
PhyloP100		1.2
PrimateAI	Uncertain	0.59	T
PROVEAN	Pathogenic	-10	D;D;D;D;D
REVEL	Benign	0.0
Sift	Pathogenic	0.0	D;D;D;D;D
Sift4G	Pathogenic	0.0010	D;D;D;D;D
Vest4		0.94
ClinPred		1.0	D
GERP RS		4.4
Varity_R		0.99
gMVP		1.0
Mutation Taster		=0/100	disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs879255109; hg19: chr19-11231059;