19-11120383-T-G

Position:

• chr19-11120383-T-G

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PM1 PM2 PM5 PP3_Strong PP5_Very_Strong

The ENST00000558518.6(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 ENST00000558518.6 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:4
• Conservation: PhyloP100: 1.17

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.

• PM1: In a hotspot region, there are 6 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 2 benign, 10 uncertain in ENST00000558518.6
• 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 id is 3689.Status of the report is reviewed_by_expert_panel, 3 stars.
• 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 [Likely_pathogenic]. Clinvar id is 252168.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-11120383-T-G is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
LDLR	NM_000527.5	c.2001T>G	p.Cys667Trp	missense_variant	14/18	ENST00000558518.6	NP_000518.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
LDLR	ENST00000558518.6	c.2001T>G	p.Cys667Trp	missense_variant	14/18	1	NM_000527.5	ENSP00000454071	P3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 35

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Hypercholesterolemia, familial, 1 Pathogenic:3

Likely pathogenic, criteria provided, single submitter	literature only	LDLR-LOVD, British Heart Foundation	Mar 25, 2016	- -
Pathogenic, criteria provided, single submitter	clinical testing	U4M - Lille University & CHRU Lille, Université de Lille - CHRU de Lille	Mar 30, 2017	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Institute of Human Genetics, University of Leipzig Medical Center	Nov 21, 2019	This variant was identified as homozygous -

LDLR-related disorder Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Jun 16, 2023

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
MutationTaster	Benign	1.0	D;D;D;D;D;D;D
PrimateAI	Uncertain	0.59	T
PROVEAN	Pathogenic	-10	D;D;D;D;D
REVEL	Pathogenic	0.94
Sift	Pathogenic	0.0	D;D;D;D;D
Sift4G	Pathogenic	0.0010	D;D;D;D;D
Polyphen		1.0	D;.;.;.;.
Vest4		0.94
MutPred		0.95		Loss of catalytic residue at C667 (P = 0.061);Loss of catalytic residue at C667 (P = 0.061);.;.;Loss of catalytic residue at C667 (P = 0.061);
MVP		1.0
MPC		0.95
ClinPred		1.0	D
GERP RS		4.4
Varity_R		0.99
gMVP		1.0

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: rs879255109; hg19: chr19-11231059;