rs775092314

Positions:

chr19-11120411-T-C

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PM1PM2PM5PP3_StrongPP5_Very_Strong

The NM_000527.5(LDLR):c.2029T>C(p.Cys677Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000372 in 1,614,082 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 Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. C677F) has been classified as Likely pathogenic.

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0000034 ( 0 hom. )

Consequence

LDLR
NM_000527.5 missense

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:9

Conservation

PhyloP100: 8.00

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 Pathogenic. Variant got 18 ACMG points.

PM1

In a disulfide_bond (size 19) in uniprot entity LDLR_HUMAN there are 24 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 chr19-11120412-G-T is described in Lovd as [Likely_pathogenic].

PP3

MetaRNN computational evidence supports a deleterious effect, 0.996

PP5

Variant 19-11120411-T-C is Pathogenic according to our data. Variant chr19-11120411-T-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 226384.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-11120411-T-C is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
LDLR	NM_000527.5 linkuse as main transcript	c.2029T>C	p.Cys677Arg	missense_variant	14/18	ENST00000558518.6	NP_000518.1	P01130-1A0A024R7D5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
LDLR	ENST00000558518.6 linkuse as main transcript	c.2029T>C	p.Cys677Arg	missense_variant	14/18	1	NM_000527.5	ENSP00000454071.1		P01130-1

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152234

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.00000398

AC:

AN:

251194

Hom.:

AF XY:

0.00

AC XY:

AN XY:

135828

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:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000880

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000342

AC:

AN:

1461848

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

727230

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:

0.00000360

Gnomad4 OTH exome

AF:

0.0000166

GnomAD4 genome

AF:

0.00000657

AC:

AN:

152234

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74376

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000147

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.00000378

ExAC

AF:

0.00000824

AC:

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:9

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Hypercholesterolemia, familial, 1

Pathogenic:4

Likely pathogenic, criteria provided, single submitter	clinical testing	Human Genome Sequencing Center Clinical Lab, Baylor College of Medicine	Apr 13, 2018	This c.2029T>C (p.Cys677Arg) variant in the LDLR gene has been reported in multiple individuals with familial hypercholesterolemia (PMID: 1301956, 10208479, 10559517) or myocardial infarction (PMID 25487149). Functional studies have indicated that the p.Cys677Arg variant in the LDLR protein has 5-15% receptor activity compared to wild-type LDLR protein (PMID: 1301956). The c.2029T>C variant is rare in the general population and cysteine at position 677 of the LDLR protein is highly evolutionarily conserved. The c.2029T>C (p.Cys677Arg) variant in the LDLR gene is classified as likely pathogenic. -
Pathogenic, no assertion criteria provided	clinical testing	Cardiovascular Genetics Laboratory, PathWest Laboratory Medicine WA - Fiona Stanley Hospital	Jun 05, 2008	- -
Likely pathogenic, criteria provided, single submitter	literature only	LDLR-LOVD, British Heart Foundation	Mar 25, 2016	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Robarts Research Institute, Western University	-	- -

not provided

Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Feb 18, 2022	Also known as FH New York-1 and p.C656R; Located within the LDL-receptor EGF precursor domain 3, and participates in disulfide bonding with another cysteine residue which is critical for correct protein structure (Sudhof et al., 1985; Rudenko et al., 2002); 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; This variant is associated with the following publications: (PMID: 10559517, 25487149, 1301956, 16389549, 17142622, 22883975, 27680772, 27765764, 31447099, 32041611, 34037665, 33087929, 2988123, 12459547, 10208479, 19487412) -
Likely pathogenic, criteria provided, single submitter	clinical testing	AiLife Diagnostics, AiLife Diagnostics	Aug 17, 2021	- -

Homozygous familial hypercholesterolemia

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Oct 11, 2019

The p.Cys677Arg variant in LDLR has been reported in at least 7 individuals with hypercholesterolemia and segregated with disease in 6 affected individuals from 1 family (Hobbs 1992, Heath 1999, Humphries 2006, Bima 2009, Hooper 2012, Martin 2016, Wang 2016). It has also been identified in 1/113610 of European chromosomes by gnomAD (http://gnomad.broadinstitute.org) and has been reported in ClinVar (Variation ID 226384). An in vitro functional study and computational prediction tools support an impact on protein function (Hobbs 1992). In summary, although additional studies are required to fully establish its clinical significance, this variant meets criteria to be classified as likely pathogenic for autosomal dominant familial . ACMG/AMP Criteria applied: PM2, PS4_Moderate, PP1_Moderate, PP3, PS3_Supporting. -

Cardiovascular phenotype

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Dec 15, 2021

The p.C677R pathogenic mutation (also known as c.2029T>C), located in coding exon 14 of the LDLR gene, results from a T to C substitution at nucleotide position 2029. The cysteine at codon 677 is replaced by arginine, an amino acid with highly dissimilar properties. This alteration was detected in conjunction with another alteration in the LDLR gene in an individual whose protein activity was 5-15% of normal (Hobbs HH et al. Hum Mutat. 1992;1(6):445-66). Subsequent studies observed this alteration in several individuals diagnosed with familial hypercholesterolemia (FH) (Humphries SE et al. J Mol Med. 2006; 84(3):203-14; Tosi I et al. Atherosclerosis. 2007;194(1):102-11). In a case report, this alteration was described to co-segregate with FH in multiple individuals in one family (Bima AI et al. Ann Clin Biochem. 2009;46(Pt 5):420-2). Another alteration affecting the same codon (p.C677Y c.2030G>A) has also been described in patients with FH (Salazar LA et al. Hum Mutat. 2002;19(4):462-3). Based on the supporting evidence, p.C677R is interpreted as a disease-causing mutation. -

Familial hypercholesterolemia

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Dec 13, 2023

This sequence change replaces cysteine, which is neutral and slightly polar, with arginine, which is basic and polar, at codon 677 of the LDLR protein (p.Cys677Arg). This variant is present in population databases (rs775092314, gnomAD 0.0009%). This missense change has been observed in individuals with hypercholesterolemia (PMID: 1301956, 10208479, 17142622, 19487412, 22883975, 27680772, 27765764). It has also been observed to segregate with disease in related individuals. This variant is also known as p.Cys656Arg. ClinVar contains an entry for this variant (Variation ID: 226384). 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 with a positive predictive value of 95%. This variant disrupts the p.Cys677 amino acid residue in LDLR. Other variant(s) that disrupt this residue have been observed in individuals with LDLR-related conditions (PMID: 9763532, 16389549, 28235710), which suggests that this may be a clinically significant amino acid residue. For these reasons, this variant has been classified as Pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

1.0

BayesDel_addAF

Pathogenic

0.58

BayesDel_noAF

Pathogenic

0.60

CADD

Pathogenic

DANN

Uncertain

0.99

DEOGEN2

Pathogenic

0.98

D;.;.;.;.

Eigen

Pathogenic

0.89

Eigen_PC

Pathogenic

0.72

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Pathogenic

0.99

D;D;D;D;D

M_CAP

Pathogenic

0.96

MetaRNN

Pathogenic

1.0

D;D;D;D;D

MetaSVM

Pathogenic

0.90

MutationAssessor

Pathogenic

4.8

H;.;.;.;H

PrimateAI

Uncertain

0.54

PROVEAN

Pathogenic

-11

D;D;D;D;D

REVEL

Pathogenic

0.96

Sift

Pathogenic

0.0

D;D;D;D;D

Sift4G

Pathogenic

0.0

D;D;D;D;D

Polyphen

1.0

D;.;.;.;.

Vest4

0.98

MutPred

0.96

Gain of disorder (P = 0.1056);Gain of disorder (P = 0.1056);.;.;Gain of disorder (P = 0.1056);

MVP

1.0

MPC

1.1

ClinPred

1.0

GERP RS

5.3

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

1.0

gMVP

1.0

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

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