19-11105507-G-C

Variant names:

• chr19-11105507-G-C
• NM_000527.5:c.601G>C

Variant summary

Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PM1 PM2 PM5 PP5_Moderate

The NM_000527.5(LDLR):​c.601G>C​(p.Glu201Gln) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. 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. E201K) has been classified as Likely pathogenic.

• Frequency: Genomes: not found (cov: 33)
• Consequence: LDLR NM_000527.5 missense
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 6.69

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 Likely_pathogenic. Variant got 8 ACMG points.

• PM1: In a strand (size 3) in uniprot entity LDLR_HUMAN there are 5 pathogenic changes around while only 0 benign (100%) 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 chr19-11105507-G-A is described in Lovd as [Likely_pathogenic].
• PP5: Variant 19-11105507-G-C is Pathogenic according to our data. Variant chr19-11105507-G-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 1968609.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
LDLR	NM_000527.5	c.601G>C	p.Glu201Gln	missense_variant	Exon 4 of 18	ENST00000558518.6	NP_000518.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
LDLR	ENST00000558518.6	c.601G>C	p.Glu201Gln	missense_variant	Exon 4 of 18	1	NM_000527.5	ENSP00000454071.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 33

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

Familial hypercholesterolemia Pathogenic:1

Nov 29, 2022

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt LDLR protein function. This variant has not been reported in the literature in individuals affected with LDLR-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces glutamic acid, which is acidic and polar, with glutamine, which is neutral and polar, at codon 201 of the LDLR protein (p.Glu201Gln). This variant disrupts the p.Glu201 amino acid residue in LDLR. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 21418584). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.20
BayesDel_addAF	Pathogenic	0.33	D
BayesDel_noAF	Pathogenic	0.24
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.77	D;.;.;.
Eigen	Uncertain	0.46
Eigen_PC	Uncertain	0.47
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Uncertain	0.87	D;D;D;D
M_CAP	Uncertain	0.26	D
MetaRNN	Uncertain	0.54	D;D;D;D
MetaSVM	Pathogenic	0.95	D
MutationAssessor	Benign	0.67	N;.;.;N
PrimateAI	Uncertain	0.49	T
PROVEAN	Uncertain	-2.4	N;N;N;N
REVEL	Pathogenic	0.74
Sift	Benign	0.089	T;T;T;T
Sift4G	Benign	0.091	T;T;D;T
Polyphen		1.0	D;.;.;.
Vest4		0.30
MutPred		0.63		Loss of disorder (P = 0.1697);Loss of disorder (P = 0.1697);.;Loss of disorder (P = 0.1697);
MVP		1.0
MPC		0.72
ClinPred		0.84	D
GERP RS		5.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.8
Varity_R		0.55
gMVP		0.91

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr19-11216183;