rs879254966

Positions:

• chr19-11116143-G-C

Variant summary

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

The NM_000527.5(LDLR):​c.1636G>C​(p.Gly546Arg) variant causes a missense change involving the alteration of a 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. G546D) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 32)
• Consequence: LDLR NM_000527.5 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:2
• Conservation: PhyloP100: 9.86

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 strand (size 5) in uniprot entity LDLR_HUMAN there are 12 pathogenic changes around while only 1 benign (92%) 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 chr19-11116144-G-A is described in Lovd as [Likely_pathogenic].
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.992
• PP5: Variant 19-11116143-G-C is Pathogenic according to our data. Variant chr19-11116143-G-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 251946.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-11116143-G-C is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
LDLR	NM_000527.5	c.1636G>C	p.Gly546Arg	missense_variant	11/18	ENST00000558518.6	NP_000518.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
LDLR	ENST00000558518.6	c.1636G>C	p.Gly546Arg	missense_variant	11/18	1	NM_000527.5	ENSP00000454071.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Hypercholesterolemia, familial, 1 Pathogenic:1

Likely pathogenic, criteria provided, single submitter

literature only

LDLR-LOVD, British Heart Foundation

Mar 25, 2016

- -

Familial hypercholesterolemia Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jun 15, 2020

This variant has been observed in individual(s) with familial hypercholesterolemia (PMID: 17539906, 22859806, Invitae). ClinVar contains an entry for this variant (Variation ID: 251946). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. This variant disrupts the p.Gly546 amino acid residue in LDLR. Other variant(s) that disrupt this residue have been observed in individuals with LDLR-related conditions (PMID: 17539906, 15823280, 29399563), which suggests that this may be a clinically significant amino acid residue. For these reasons, this variant has been classified as Pathogenic. This variant is not present in population databases (ExAC no frequency). This sequence change replaces glycine with arginine at codon 546 of the LDLR protein (p.Gly546Arg). The glycine residue is highly conserved and there is a moderate physicochemical difference between glycine and arginine. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.95
BayesDel_addAF	Pathogenic	0.46	D
BayesDel_noAF	Pathogenic	0.42
CADD	Pathogenic	29
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.90	D;.;.;.;.;.
Eigen	Uncertain	0.43
Eigen_PC	Uncertain	0.39
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.99	D;D;D;D;D;D
M_CAP	Pathogenic	0.76	D
MetaRNN	Pathogenic	0.99	D;D;D;D;D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Uncertain	2.5	M;.;.;.;.;M
PrimateAI	Uncertain	0.66	T
PROVEAN	Pathogenic	-7.4	D;D;D;D;D;D
REVEL	Pathogenic	0.84
Sift	Uncertain	0.0070	D;D;D;D;D;D
Sift4G	Pathogenic	0.0	D;D;D;D;D;D
Polyphen		0.96	D;.;.;.;.;.
Vest4		0.85
MutPred		0.95		Gain of methylation at G546 (P = 0.037);Gain of methylation at G546 (P = 0.037);.;.;.;Gain of methylation at G546 (P = 0.037);
MVP		1.0
MPC		0.89
ClinPred		1.0	D
GERP RS		4.9
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.8
Varity_R		0.95
gMVP		0.97

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		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: rs879254966; hg19: chr19-11226819;