rs879254589

Variant names:

• chr19-11105507-G-A
• rs879254589
• NM_000527.5:c.601G>A

Your query was ambiguous. Multiple possible variants found:

• chr19-11105507-G-A
• chr19-11105507-G-C

Variant summary

Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PM1 PM2 PP3_Strong PP5_Very_Strong

The NM_000527.5(LDLR):​c.601G>A​(p.Glu201Lys) variant causes a missense change. 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 (★★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: LDLR NM_000527.5 missense
• Clinical Significance: Likely pathogenic criteria provided, multiple submitters, no conflicts P:4
• 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 Pathogenic. Variant got 16 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
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.951
• PP5: Variant 19-11105507-G-A is Pathogenic according to our data. Variant chr19-11105507-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 251317.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-11105507-G-A is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
LDLR	NM_000527.5	c.601G>A	p.Glu201Lys	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>A	p.Glu201Lys	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

Bravo AF: 0.00000756

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Hypercholesterolemia, familial, 1 Pathogenic:3

Mar 01, 2016

Iberoamerican FH Network

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: research

- -

Mar 25, 2016

LDLR-LOVD, British Heart Foundation

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: literature only;research

- -

Sep 23, 2024

All of Us Research Program, National Institutes of Health

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.601G>A (p.Glu201Lys) variant, also known as p.Glu180Lys in LDLR gene, that encodes for low density lipoprotein receptor, has been identified in several unrelated individuals (>10) affected with familial hypercholesterolemia (FH) (PMID: 21418584, 20019594, 32770674, 33391333). This variant lies in the mutational hot spot (amino acids 105-232) of a well-established functional domain critical for LDLR protein function. In-silico computational prediction tools suggest that the p.Glu201Lys variant may have deleterious effect on the protein function (REVEL score: 0.885). This variant is absent in the general population database, gnomAD and interpreted as likely pathogenic by multiple submitters in the ClinVar database (ClinVar ID: 251317). Therefore, the c.601G>A (p.Glu201Lys) variant in LDLR gene is classified as likely pathogenic. -

not provided Pathogenic:1

Dec 10, 2021

GeneDx

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Also known as p.Glu180Lys; This variant is associated with the following publications: (PMID: 21418584, 20019594, 32770674) -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.62
BayesDel_addAF	Pathogenic	0.49	D
BayesDel_noAF	Pathogenic	0.47
CADD	Uncertain	25
DANN	Pathogenic	1.0
DEOGEN2	Pathogenic	0.85	D;.;.;.
Eigen	Uncertain	0.67
Eigen_PC	Uncertain	0.61
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Uncertain	0.93	D;D;D;D
M_CAP	Pathogenic	0.54	D
MetaRNN	Pathogenic	0.95	D;D;D;D
MetaSVM	Pathogenic	1.0	D
MutationAssessor	Uncertain	2.3	M;.;.;M
PrimateAI	Uncertain	0.57	T
PROVEAN	Uncertain	-3.5	D;D;D;D
REVEL	Pathogenic	0.89
Sift	Benign	0.043	D;D;D;D
Sift4G	Uncertain	0.025	D;D;D;D
Polyphen		1.0	D;.;.;.
Vest4		0.58
MutPred		0.78		Gain of methylation at E201 (P = 0.0019);Gain of methylation at E201 (P = 0.0019);.;Gain of methylation at E201 (P = 0.0019);
MVP		1.0
MPC		0.84
ClinPred		0.98	D
GERP RS		5.6
Varity_R		0.79
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: rs879254589; hg19: chr19-11216183; COSMIC: COSV52942362; COSMIC: COSV52942362;