rs193922570

Positions:

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2PP4PP3

This summary comes from the ClinGen Evidence Repository: The NM_000527.5 (LDLR): c.2113G>C (p.Ala705Pro) variant is classified as Uncertain significance - insufficient evidence for Familial Hypercholesterolemia by applying evidence codes (PM2, PP4, PP3) as defined by the ClinGen Familial Hypercholesterolemia Expert Panel LDLR-specific variant curation guidelines (https://doi.org/10.1016/j.gim.2021.09.012).The supporting evidence is as follows:PM2 Met: PopMAX MAF = 0.00001 in European (Non-Finnish) population in gnomAD (gnomAD v2.1.1).PP4 Met: This variant meets PM2 and is identified in 1 index case who met clinical criteria for FH after alternative causes for high cholesterol were excluded (Department of Vascular Medicine, Academic Medical Center at the University of Amsterdam, Amsterdam, The Netherlands, PMID 11810272).PP3 Met: REVEL score = 0.78, which is above the threshold of 0.75.PS3 not met: There is no functional experiment reported for this variant. PM5 not met: There is one other variant in the same codon: LDLR: NM_000527:c.2113G>T (p.Ala705Ser) is classified as Uncertain significance - insufficient evidence by these guidelines. Therefore PM5 is not met. LINK:https://erepo.genome.network/evrepo/ui/classification/CA023637/MONDO:0007750/013

Frequency

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

Consequence

LDLR
NM_000527.5 missense

Scores

Clinical Significance

Uncertain significance reviewed by expert panel P:8U:3

Conservation

PhyloP100: 6.83

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 Uncertain_significance. Variant got 4 ACMG points.

PM2

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 linkuse as main transcript	c.2113G>C	p.Ala705Pro	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.2113G>C	p.Ala705Pro	missense_variant	14/18	1	NM_000527.5	ENSP00000454071.1		P01130-1

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152140

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:

0.00000399

AC:

AN:

250870

Hom.:

AF XY:

0.00000737

AC XY:

AN XY:

135684

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

Cov.:

GnomAD4 genome

AF:

0.00000657

AC:

AN:

152140

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74320

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

ClinVar

Significance: Uncertain significance

Submissions summary: Pathogenic:8Uncertain:3

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

Hypercholesterolemia, familial, 1

Pathogenic:3Uncertain:3

Pathogenic, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Uncertain significance, reviewed by expert panel	curation	ClinGen Familial Hypercholesterolemia Variant Curation Expert Panel	Feb 11, 2022	The NM_000527.5 (LDLR): c.2113G>C (p.Ala705Pro) variant is classified as Uncertain significance - insufficient evidence for Familial Hypercholesterolemia by applying evidence codes (PM2, PP4, PP3) as defined by the ClinGen Familial Hypercholesterolemia Expert Panel LDLR-specific variant curation guidelines (https://doi.org/10.1016/j.gim.2021.09.012). The supporting evidence is as follows: PM2 Met: PopMAX MAF = 0.00001 in European (Non-Finnish) population in gnomAD (gnomAD v2.1.1). PP4 Met: This variant meets PM2 and is identified in 1 index case who met clinical criteria for FH after alternative causes for high cholesterol were excluded (Department of Vascular Medicine, Academic Medical Center at the University of Amsterdam, Amsterdam, The Netherlands, PMID 11810272). PP3 Met: REVEL score = 0.78, which is above the threshold of 0.75. PS3 not met: There is no functional experiment reported for this variant. PM5 not met: There is one other variant in the same codon: LDLR: NM_000527:c.2113G>T (p.Ala705Ser) is classified as Uncertain significance - insufficient evidence by these guidelines. Therefore PM5 is not met. -
Pathogenic, no assertion criteria provided	research	Laboratorium voor Moleculaire Diagnostiek Experimentele Vasculaire Geneeskunde, Academisch Medisch Centrum	-	- -
Uncertain significance, criteria provided, single submitter	clinical testing	All of Us Research Program, National Institutes of Health	Dec 01, 2023	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	May 22, 2023	- -
Uncertain significance, criteria provided, single submitter	literature only	LDLR-LOVD, British Heart Foundation	Mar 25, 2016	- -

not provided

Pathogenic:2

Likely pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Nov 21, 2024	Identified in many individuals with FH referred for genetic testing at GeneDx and in published literature (PMID: 11810272, 18325082, 20506408, 21382890, 23375686, 23833242); A large study of individuals from the Netherlands with FH-related variants concluded that LDL-C levels were significantly higher in p.(A705P) carriers compared to non-carriers (PMID: 20506408); 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.(A684P); This variant is associated with the following publications: (PMID: 18325082, 21382890, 23375686, 22390909, 21642693, 22095935, 23833242, 27919364, 23369702, 25412742, 20506408, 11810272, 34037665, 32719484, 38225666) -
Pathogenic, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -

Familial hypercholesterolemia

Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 16, 2024	This sequence change replaces alanine, which is neutral and non-polar, with proline, which is neutral and non-polar, at codon 705 of the LDLR protein (p.Ala705Pro). This variant is present in population databases (rs193922570, gnomAD 0.0009%). This missense change has been observed in individuals with familial hypercholesterolemia (PMID: 11810272, 18325082, 21382890, 22095935, 23375686, 25412742). This variant is also known as p.A684P. ClinVar contains an entry for this variant (Variation ID: 36459). 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.Ala705 amino acid residue in LDLR. Other variant(s) that disrupt this residue have been observed in individuals with LDLR-related conditions (PMID: 15556093), which suggests that this may be a clinically significant amino acid residue. For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Sep 25, 2017	Variant summary: The c.2113G>C (p.Ala705Pro) in LDLR gene is a missense variant involves a highly conserved nucleotide and 2/4 in silico tools (SNPsandGO not captured here due to low reliability index value) predict deleterious outcome. However, no functional studies supporting these predictions were published at the time of evaluation. The c.2113G>C is present in the control population dataset of gnomAD at a low frequency of 0.000004 (1/245716 chromosomes tested). The observed frequency does not exceed the maximum expected allele frequency for a pathogenic variant of 0.0012, suggesting that it is not a common polymorphism. The variant has been reported in multiple affected individuals with FH, including one patient, who carried R3500Q in APOB with lipid profile suggestive of being a carrier of two pathogenic variants. The variant reportedly classified as having a delayed (2B) transport from the endoplasmic reticulum to the cell surface, but is cited as VUS by reputable databases/clinical laboratories. Lastly, the codon Ala705 appears to be a hot spot, and another alteration, c.2113G>T (p.Ala705Ser) has been reported in association with Hypercholesterolaemia. Taken together the variant was classified as Pathogenic. -

Cardiovascular phenotype

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Oct 01, 2021

The p.A705P pathogenic mutation (also known as c.2113G>C), located in coding exon 14 of the LDLR gene, results from a G to C substitution at nucleotide position 2113. The alanine at codon 705 is replaced by proline, an amino acid with highly similar properties. This alteration, also referred to as A684P, has been detected in multiple individuals from Dutch familial hypercholesterolemia (FH) cohorts with elevated mean LDL-C level compared to controls; however, in some cases, clinical details were limited (Fouchier SW et al. Hum Genet. 2001;109:602-15; Huijgen R et al. Circ Cardiovasc Genet. 2011;4:413-7; van der Graaf A et al. Circulation. 2011;123:1167-73). This alteration was also seen in an Italian FH cohort (Bertolini S et al. Atherosclerosis. 2013;227:342-8). In one family, this alteration segregated with hypercholesterolemia in two individuals, but was also detected in two relatives without elevated cholesterol (Huijgen R et al. Hum Mutat. 2012;33:448-55). In another report, this alteration was seen in conjunction with an APOB mutation in a patient with untreated LDL-C level of 9.6mmol/L (Sjouke B et al. J Clin Lipidol. 2016;10:1462-1469). Another alteration affecting this amino acid (p.A705S) has also been detected in an FH cohort (Humphries SE. J Med Genet. 2006;43(12):943-9). In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.71

BayesDel_addAF

Pathogenic

0.52

BayesDel_noAF

Pathogenic

0.50

CADD

Uncertain

DANN

Uncertain

1.0

DEOGEN2

Pathogenic

0.85

D;.;.;.;.

Eigen

Uncertain

0.34

Eigen_PC

Uncertain

0.39

FATHMM_MKL

Pathogenic

1.0

LIST_S2

Uncertain

0.94

D;D;D;D;D

M_CAP

Pathogenic

0.68

MetaRNN

Pathogenic

0.87

D;D;D;D;D

MetaSVM

Pathogenic

0.97

MutationAssessor

Pathogenic

3.2

M;.;.;.;M

PrimateAI

Uncertain

0.52

PROVEAN

Uncertain

-2.7

D;D;D;D;D

REVEL

Pathogenic

0.78

Sift

Benign

0.097

T;T;T;T;T

Sift4G

Benign

0.27

T;T;T;T;T

Polyphen

0.12

B;.;.;.;.

Vest4

0.72

MVP

1.0

MPC

0.36

ClinPred

0.91

GERP RS

5.3

Varity_R

0.95

gMVP

0.94

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