rs770744861

Positions:

chr19-11120405-G-A

Variant summary

Our verdict is Likely pathogenic. Variant got 9 ACMG points: 9P and 0B. PP3PP4PS4_SupportingPP1_StrongPM2

This summary comes from the ClinGen Evidence Repository: The NM_000527.5(LDLR):c.2023G>A (p.Gly675Ser) variant is classified as Likely Pathogenic for Familial Hypercholesterolemia by applying ACMG/AMP evidence codes PP1_Strong, PM2, PP3, PP4 and PS4_Supporting as defined by the ClinGen Familial Hypercholesterolemia Expert Panel LDLR-specific variant curation guidelines (specification version 1.2) on 2 July 2024. The supporting evidence is as follows: PM2: PopMax MAF = 0.000008856 (0.0008856%) in European (non-Finnish) exomes (gnomAD v2.1.1). PP3: REVEL = 0.853. PS4_Supporting, PP4: Variant meets PM2 and is identified in at least 5 unrelated index cases who fulfill criteria for FH (2 cases with possible FH by Simon Broome criteria and 2 cases with DLCN score >=6 from Molecular Genetics Laboratory, Centre for Cardiovascular Surgery and Transplantation, Czech Republic, and PMID 22698793; 1 case from PMID 27824480). PP1_Strong: Variant segregates with FH phenotype in at least 8 informative meioses from 4 families (Molecular Genetics Laboratory, Centre for Cardiovascular Surgery and Transplantation, Czech Republic): 5 affected family members have the variant and 3 unaffected family members do not have the variant. LINK:https://erepo.genome.network/evrepo/ui/classification/CA038175/MONDO:0007750/013

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000034 ( 0 hom. )

Consequence

LDLR
NM_000527.5 missense

Scores

9

8

2

Clinical Significance

Likely pathogenic reviewed by expert panel P:4U:3

Conservation

PhyloP100: 7.89

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.

PS4

For more information check the summary or visit ClinGen Evidence Repository.

PM2

For more information check the summary or visit ClinGen Evidence Repository.

PP1

For more information check the summary or visit ClinGen Evidence Repository.

PP3

For more information check the summary or visit ClinGen Evidence Repository.

PP4

For more information check the summary or visit ClinGen Evidence Repository.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
LDLR	NM_000527.5 link	c.2023G>A	p.Gly675Ser	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 link	c.2023G>A	p.Gly675Ser	missense_variant	14/18	1	NM_000527.5	ENSP00000454071.1		P01130-1

Frequencies

GnomAD3 genomes

Cov.:

32

GnomAD3 exomes

AF:

0.00000400

AC:

1

AN:

249908

Hom.:

0

AF XY:

0.00

AC XY:

0

AN XY:

135398

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:

0.00000886

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000342

AC:

5

AN:

1461586

Hom.:

0

Cov.:

35

AF XY:

0.00000413

AC XY:

3

AN XY:

727128

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:

0.00000450

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

32

ExAC

AF:

0.00000824

AC:

1

EpiCase

AF:

0.00

EpiControl

AF:

0.0000593

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:4Uncertain:3

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

Hypercholesterolemia, familial, 1

Pathogenic:3

Likely pathogenic, reviewed by expert panel	curation	ClinGen Familial Hypercholesterolemia Variant Curation Expert Panel	Jul 02, 2024	The NM_000527.5(LDLR):c.2023G>A (p.Gly675Ser) variant is classified as Likely Pathogenic for Familial Hypercholesterolemia by applying ACMG/AMP evidence codes PP1_Strong, PM2, PP3, PP4 and PS4_Supporting as defined by the ClinGen Familial Hypercholesterolemia Expert Panel LDLR-specific variant curation guidelines (specification version 1.2) on 2 July 2024. The supporting evidence is as follows: PM2: PopMax MAF = 0.000008856 (0.0008856%) in European (non-Finnish) exomes (gnomAD v2.1.1). PP3: REVEL = 0.853. PS4_Supporting, PP4: Variant meets PM2 and is identified in at least 5 unrelated index cases who fulfill criteria for FH (2 cases with possible FH by Simon Broome criteria and 2 cases with DLCN score >=6 from Molecular Genetics Laboratory, Centre for Cardiovascular Surgery and Transplantation, Czech Republic, and PMID 22698793; 1 case from PMID 27824480). PP1_Strong: Variant segregates with FH phenotype in at least 8 informative meioses from 4 families (Molecular Genetics Laboratory, Centre for Cardiovascular Surgery and Transplantation, Czech Republic): 5 affected family members have the variant and 3 unaffected family members do not have the variant. -
Likely pathogenic, criteria provided, single submitter	clinical testing	Molecular Genetics Laboratory, Centre for Cardiovascular Surgery and Transplantation	Nov 05, 2016	- -
Likely pathogenic, criteria provided, single submitter	literature only	LDLR-LOVD, British Heart Foundation	Mar 25, 2016	- -

Familial hypercholesterolemia

Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Jan 31, 2023	This missense variant (also known as p.Gly654Ser in the mature protein) replaces glycine with serine at codon 675 of the LDLR protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in individuals affected with familial hypercholesterolemia (PMID: 11754108, 21310417, 22698793, 27824480). This variant has been identified in 1/249908 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. -
Uncertain significance, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Aug 27, 2021	This sequence change replaces glycine with serine at codon 675 of the LDLR protein (p.Gly675Ser). The glycine residue is highly conserved and there is a small physicochemical difference between glycine and serine. This variant is present in population databases (rs770744861, ExAC 0.002%). This missense change has been observed in individuals with familial hypercholesterolemia (PMID: 11754108, 22698793, 27824480). This variant is also known as p.Gly654Ser. ClinVar contains an entry for this variant (Variation ID: 252173). 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. 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. -

Cardiovascular phenotype

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

May 04, 2018

The p.G675S variant (also known as c.2023G>A), located in coding exon 14 of the LDLR gene, results from a G to A substitution at nucleotide position 2023. The glycine at codon 675 is replaced by serine, an amino acid with similar properties. This alteration has been reported in individuals with familial hypercholesterolemia (Kuhrová V et al. Hum. Mutat., 2002 Jan;19:80; Tichý L et al. Atherosclerosis, 2012 Aug;223:401-8). Based on internal structural analysis, this variant is anticipated to result in a significant decrease in structural stability. This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the majority of available evidence to date, this variant is likely to be pathogenic. -

not provided

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

GeneDx

Jun 06, 2024

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; Reported in association with familial hypercholesterolemia (FH) in published literature (PMID: 11524740, 11754108); Also known as p.(G654S); This variant is associated with the following publications: (PMID: 25487149, 11524740, 11754108) -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.43

BayesDel_addAF

Pathogenic

0.48

D

BayesDel_noAF

Pathogenic

0.45

CADD

Uncertain

26

DANN

Uncertain

1.0

DEOGEN2

Pathogenic

0.90

D;.;.;.;.

Eigen

Uncertain

0.57

Eigen_PC

Uncertain

0.42

FATHMM_MKL

Pathogenic

0.99

D

LIST_S2

Uncertain

0.89

D;D;D;D;D

M_CAP

Pathogenic

0.76

D

MetaRNN

Pathogenic

0.99

D;D;D;D;D

MetaSVM

Pathogenic

1.1

D

MutationAssessor

Uncertain

2.9

M;.;.;.;M

PrimateAI

Benign

0.44

T

PROVEAN

Pathogenic

-5.6

D;D;D;D;D

REVEL

Pathogenic

0.85

Sift

Uncertain

0.0060

D;D;D;D;D

Sift4G

Uncertain

0.0020

D;D;D;D;D

Polyphen

0.85

P;.;.;.;.

Vest4

0.74

MutPred

0.91

Gain of glycosylation at G675 (P = 0.0225);Gain of glycosylation at G675 (P = 0.0225);.;.;Gain of glycosylation at G675 (P = 0.0225);

MVP

1.0

MPC

0.54

ClinPred

0.98

D

GERP RS

5.3

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.91

gMVP

0.92

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.060

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.

Other links and lift over

dbSNP: rs770744861; hg19: chr19-11231081;