rs879254756

Variant names:

Variant summary

Our verdict is Likely pathogenic. Variant got 9 ACMG points: 9P and 0B. PM1PM2PP3_StrongPP5

The NM_000527.5(LDLR):c.1016T>C(p.Leu339Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,530 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: 32)

Exomes 𝑓: 6.8e-7 ( 0 hom. )

Consequence

LDLR
NM_000527.5 missense

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:7U:1

Conservation

PhyloP100: 0.929

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:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_pathogenic. Variant got 9 ACMG points.

PM1

In a strand (size 2) in uniprot entity LDLR_HUMAN there are 9 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, 0.957

PP5

Variant 19-11110727-T-C is Pathogenic according to our data. Variant chr19-11110727-T-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 251597.We mark this variant Likely_pathogenic, oryginal submissions are: {Likely_pathogenic=4, Uncertain_significance=1, Pathogenic=3}. Variant chr19-11110727-T-C is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
LDLR	NM_000527.5 link	c.1016T>C	p.Leu339Pro	missense_variant	Exon 7 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.1016T>C	p.Leu339Pro	missense_variant	Exon 7 of 18	1	NM_000527.5	ENSP00000454071.1		P01130-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

6.84e-7

AC:

AN:

1461530

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

727064

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:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.0000166

GnomAD4 genome

Cov.:

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:7Uncertain:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Hypercholesterolemia, familial, 1

Pathogenic:3

Mar 01, 2016

Laboratory of Genetics and Molecular Cardiology, University of São Paulo

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

- -

Juno Genomics, Hangzhou Juno Genomics, Inc

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

PM2_Supporting+PS4+PP4 -

Familial hypercholesterolemia

Pathogenic:2

Nov 29, 2021

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: LDLR c.1016T>C (p.Leu339Pro) results in a non-conservative amino acid change located in the EGF like Domain (IPR000742) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 251028 control chromosomes (gnomAD). c.1016T>C has been reported in the literature in multiple individuals affected with Familial Hypercholesterolemia and was reported to segregate with disease in affected family members (Chiou_2010 & 2017, Chan_2018, Huang_2021). These data indicate that the variant is very likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Two ClinVar submitters (evaluation after 2014) cite the variant as likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -

Dec 27, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces leucine, which is neutral and non-polar, with proline, which is neutral and non-polar, at codon 339 of the LDLR protein (p.Leu339Pro). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with familial hypercholesterolemia (PMID: 20538126, 30592178; internal data). This variant is also known as p.P318L. ClinVar contains an entry for this variant (Variation ID: 251597). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is expected to disrupt LDLR protein function with a positive predictive value of 95%. For these reasons, this variant has been classified as Pathogenic. -

not provided

Pathogenic:1Uncertain:1

Feb 07, 2023

Quest Diagnostics Nichols Institute San Juan Capistrano

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant has not been reported in large, multi-ethnic general populations (http://gnomad.broadinstitute.org). In the published literature, the variant has been reported in multiple individuals affected with familial hypercholesterolemia (FH) (PMID: 20538126 (2010), 21376320 (2011), 28502495 (2017), 30592178 (2019), 30592178 (2021)). Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded predictions that this variant is damaging. Based on the available information, this variant is classified as pathogenic. -

Feb 18, 2022

Mayo Clinic Laboratories, Mayo Clinic

Significance: Uncertain significance

Review Status: flagged submission

Collection Method: clinical testing

PP1_moderate, PM2_supporting, PS4_moderate -

Cardiovascular phenotype

Pathogenic:1

Jan 08, 2024

Ambry Genetics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1016T>C (p.L339P) alteration is located in exon 7 (coding exon 7) of the LDLR gene. This alteration results from a T to C substitution at nucleotide position 1016, causing the leucine (L) at amino acid position 339 to be replaced by a proline (P). This variant was not reported in population-based cohorts in the Genome Aggregation Database (gnomAD). This alteration, which is also reported as p.L318P, has been detected in individuals with familial hypercholesterolemia (FH), specifically of East Asian ancestry (Chiou, 2010; Chan, 2019). Additionally, this alteration was detected as compound heterozygous with additional alterations in LDLR in individuals with concerns for homozygous FH (Du, 2022). This amino acid position is not well conserved in available vertebrate species. This alteration is predicted to be deleterious by in silico analysis. Based on the available evidence, this alteration is classified as likely pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.71

BayesDel_addAF

Pathogenic

0.44

BayesDel_noAF

Pathogenic

0.39

CADD

Benign

DANN

Uncertain

0.99

DEOGEN2

Uncertain

0.71

D;.;.;.;.;.

Eigen

Benign

-0.13

Eigen_PC

Benign

-0.27

FATHMM_MKL

Benign

0.68

LIST_S2

Benign

0.85

T;T;D;T;D;T

M_CAP

Pathogenic

0.77

MetaRNN

Pathogenic

0.96

D;D;D;D;D;D

MetaSVM

Uncertain

0.72

MutationAssessor

Uncertain

2.3

M;.;.;.;.;M

PrimateAI

Benign

0.34

PROVEAN

Benign

-2.3

N;N;N;N;N;N

REVEL

Pathogenic

0.67

Sift

Benign

0.29

T;T;T;T;T;T

Sift4G

Benign

0.15

T;T;T;T;T;T

Polyphen

0.94

P;.;.;.;.;.

Vest4

0.82

MutPred

0.55

Gain of disorder (P = 0.0286);Gain of disorder (P = 0.0286);.;.;.;Gain of disorder (P = 0.0286);

MVP

1.0

MPC

0.84

ClinPred

0.82

GERP RS

3.3

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.81

gMVP

0.98

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

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