rs869320648

Variant names:

Variant summary

Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PM1PM2PP3_ModeratePP5

The NM_000527.5(LDLR):c.355G>A(p.Gly119Arg) variant causes a missense change. The variant allele was found at a frequency of 0.00000137 in 1,461,338 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 0.0000014 ( 0 hom. )

Consequence

LDLR
NM_000527.5 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1U:1

Conservation

PhyloP100: 4.83

Variant links:

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 links:

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ACMG classification

Classification made for transcript

Verdict is Likely_pathogenic. Variant got 7 ACMG points.

PM1

In a disulfide_bond (size 12) in uniprot entity LDLR_HUMAN there are 22 pathogenic changes around while only 1 benign (96%) in NM_000527.5

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.872

PP5

Variant 19-11105261-G-A is Pathogenic according to our data. Variant chr19-11105261-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 225179.We mark this variant Likely_pathogenic, oryginal submissions are: {Likely_pathogenic=1, Uncertain_significance=1}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
LDLR	NM_000527.5 link	c.355G>A	p.Gly119Arg	missense_variant	Exon 4 of 18	ENST00000558518.6	NP_000518.1	P01130-1A0A024R7D5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
LDLR	ENST00000558518.6 link	c.355G>A	p.Gly119Arg	missense_variant	Exon 4 of 18	1	NM_000527.5	ENSP00000454071.1		P01130-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.00000398

AC:

AN:

251020

Hom.:

AF XY:

0.00000736

AC XY:

AN XY:

135832

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000327

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000137

AC:

AN:

1461338

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

726982

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000232

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1Uncertain:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Hypercholesterolemia, familial, 1

Pathogenic:1

Apr 03, 2016

SNPedia

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: literature only

- -

Familial hypercholesterolemia

Uncertain:1

Apr 28, 2022

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. 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. ClinVar contains an entry for this variant (Variation ID: 225179). This missense change has been observed in individual(s) with clinical features of LDLR-related conditions and/or LDLR-related conditions (PMID: 27050191; Invitae). This variant is present in population databases (no rsID available, gnomAD 0.003%). This sequence change replaces glycine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 119 of the LDLR protein (p.Gly119Arg). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.37

BayesDel_addAF

Pathogenic

0.38

BayesDel_noAF

Pathogenic

0.40

CADD

Uncertain

DANN

Uncertain

1.0

DEOGEN2

Pathogenic

0.87

D;.;.;.

Eigen

Uncertain

0.37

Eigen_PC

Uncertain

0.27

FATHMM_MKL

Pathogenic

1.0

LIST_S2

Uncertain

0.96

D;D;D;D

M_CAP

Pathogenic

0.40

MetaRNN

Pathogenic

0.87

D;D;D;D

MetaSVM

Pathogenic

0.90

MutationAssessor

Uncertain

2.7

M;.;.;M

PrimateAI

Benign

0.47

PROVEAN

Uncertain

-4.1

D;D;D;D

REVEL

Pathogenic

0.76

Sift

Benign

0.083

T;D;D;T

Sift4G

Benign

0.18

T;T;T;T

Polyphen

0.80

P;.;.;.

Vest4

0.69

MutPred

0.65

Gain of ubiquitination at K120 (P = 0.1295);Gain of ubiquitination at K120 (P = 0.1295);.;Gain of ubiquitination at K120 (P = 0.1295);

MVP

1.0

MPC

0.72

ClinPred

0.96

GERP RS

5.3

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.8

Varity_R

0.58

gMVP

0.97

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.11

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over