19-11105315-G-A

Position:

chr19-11105315-G-A

Variant summary

Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PM1PM2PM5PP3_StrongPP5

The NM_000527.5(LDLR):c.409G>A(p.Gly137Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000116 in 1,461,528 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G137C) has been classified as Likely pathogenic.

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 0.000012 ( 1 hom. )

Consequence

LDLR
NM_000527.5 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:7U:1O:1

Conservation

PhyloP100: 9.88

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 11 ACMG points.

PM1

In a disulfide_bond (size 15) in uniprot entity LDLR_HUMAN there are 28 pathogenic changes around while only 2 benign (93%) 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 chr19-11105315-G-T is described in Lovd as [Likely_pathogenic].

PP3

MetaRNN computational evidence supports a deleterious effect, 0.979

PP5

Variant 19-11105315-G-A is Pathogenic according to our data. Variant chr19-11105315-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 183087.We mark this variant Likely_pathogenic, oryginal submissions are: {Uncertain_significance=1, Pathogenic=1, not_provided=1, Likely_pathogenic=4}. Variant chr19-11105315-G-A 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.409G>A	p.Gly137Ser	missense_variant	4/18	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.409G>A	p.Gly137Ser	missense_variant	4/18	1	NM_000527.5	ENSP00000454071.1		P01130-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.0000159

AC:

AN:

251184

Hom.:

AF XY:

0.0000221

AC XY:

AN XY:

135852

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.0000993

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000327

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000880

Gnomad OTH exome

AF:

0.000163

GnomAD4 exome

AF:

0.0000116

AC:

AN:

1461528

Hom.:

Cov.:

AF XY:

0.00000963

AC XY:

AN XY:

727104

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.000191

Gnomad4 EAS exome

AF:

0.0000252

Gnomad4 SAS exome

AF:

0.0000580

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000360

Gnomad4 OTH exome

AF:

0.0000331

GnomAD4 genome

Cov.:

ExAC

AF:

0.00000824

AC:

EpiCase

AF:

0.00

EpiControl

AF:

0.0000593

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:7Uncertain:1Other:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Hypercholesterolemia, familial, 1

Pathogenic:3

Likely pathogenic, criteria provided, single submitter	literature only	LDLR-LOVD, British Heart Foundation	Mar 25, 2016	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Molecular Genetics Laboratory, Centre for Cardiovascular Surgery and Transplantation	Nov 05, 2016	- -
Pathogenic, no assertion criteria provided	research	Laboratorium voor Moleculaire Diagnostiek Experimentele Vasculaire Geneeskunde, Academisch Medisch Centrum	-	- -

not provided

Pathogenic:1Uncertain:1Other:1

Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Jun 20, 2024	Identified in a patient with familial hypercholesterolemia and in a second patient with myocardial infarction, however, additional clinical and segregation information was not included (PMID: 15823288, 25414273); Functional studies have inconsistent results; while one study shows this variant leads to reduced binding activity, another analysis indicates that G137S has no effect on LDL uptake compared to wild type (PMID: 25647241, 25414273); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 25487149, 29431662, 28286704, 26321433, 22683370, 30583242, 37937776, 36580209, 25647241, 15823288, 36969703, 36190978, 36267056, 34407635, 33740630, 25414273, 34906454) -
not provided, no classification provided	in vitro	Dept. of Genetics and Pharmacogenomics, Merck Research Labs	-	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Dec 01, 2019	- -

LDLR-related disorder

Pathogenic:1

Likely pathogenic, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Jun 13, 2024

The LDLR c.409G>A variant is predicted to result in the amino acid substitution p.Gly137Ser. This variant has been reported in patients with hypercholesterolemia (reported as G116S in Damgaard et al. 2005. PubMed ID: 15823288; Dubé et al. 2015. PubMed ID: 25414273; Jensson et al. 2023. PubMed ID: 37937776). One functional study showed this variant caused 60% reduced ligand binding activity compared to wild-type (Dubé et al. 2015. PubMed ID: 25414273) whereas another study showed no effect on LDL uptake (Thormaehlen et al. 2015. PubMed ID: 25647241). Of note, other missense variants affecting the same amino acid (p.Gly137Val, p.Gly137Cys) have also been reported to be pathogenic for hypercholesterolemia (HGMD). This variant is interpreted as likely pathogenic. -

Cardiovascular phenotype

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Aug 15, 2023

The p.G137S variant (also known as c.409G>A), located in coding exon 4 of the LDLR gene, results from a G to A substitution at nucleotide position 409. The glycine at codon 137 is replaced by serine, an amino acid with similar properties. This alteration, which is also known as p.G116S, has been reported in familial hypercholesterolemia (FH) cohorts, including a case control study of the Inuit population (Damgaard D et al. Atherosclerosis, 2005 May;180:155-60; Cameron J et al. Transl Res, 2012 Aug;160:125-30; Dubé JB et al. Circ Cardiovasc Genet, 2015 Feb;8:100-5; Björnsson E et al. Arterioscler Thromb Vasc Biol, 2021 Oct;41:2616-2628; Leren TP et al. Atherosclerosis, 2021 Apr;322:61-66; Jørsboe E et al. HGG Adv, 2022 Oct;3:100118). An in vitro study showed this alteration had reduction in ligand binding compared to wild-type (Dubé JB et al. Circ Cardiovasc Genet, 2015 Feb;8:100-5). Internal structural analysis demonstrated this alteration is moderately destabilizing to the local structure (Ambry internal data). 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. -

Familial hypercholesterolemia

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

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

Oct 30, 2023

Variant summary: LDLR c.409G>A (p.Gly137Ser) results in a non-conservative amino acid change located in the Low-density lipoprotein (LDL) receptor class A repeat (IPR002172) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 1.6e-05 in 251184 control chromosomes. c.409G>A has been reported in the literature in multiple individuals affected with Familial Hypercholesterolemia (example, Cameron_2012, Damgaard_2005, Dube_2015, Leren_2021). These data indicate that the variant is very likely to be associated with disease. One study (Dube_2015) determined the frequency of the variant in Inuit general population from Alaska, Canada and Greenland to be relatively high at 10%. Authors stratified plasma lipoprotein profiles according to LDLR p.Gly137Ser genotype and determined that carriers had approximately a 3-fold increased risk of hypercholesterolemia, but did not have classical familial hypercholesterolemia. They finally concluded that the variant is a common, dysfunctional variant in Inuit that is strongly associated with a large LDL cholesterol-raising effect, although not causing classical FH. Another study has further corroborated these findings reporting this variant as conferring a high risk for familial hypercholesterolemia in 30% of Greenlanders (example, Jorsboe_2022). At least two publications report conflicting experimental evidence evaluating an impact on protein function. One study demonstrated the variant to confer no effect on LDL uptake (Thormaehlen_2015) while another study determined it caused a significant 61% reduction in LDL binding ability (Dube_2015). The following publications have been ascertained in the context of this evaluation (PMID: 22683370, 15823288, 25414273, 36267056, 33740630, 25647241). Four submitters have cited clinical-significance assessments for this variant to ClinVar after 2014 (LP, n=3). Based on the evidence outlined above, the variant was classified as pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.16

BayesDel_addAF

Pathogenic

0.46

BayesDel_noAF

Pathogenic

0.52

CADD

Uncertain

DANN

Uncertain

1.0

DEOGEN2

Pathogenic

0.88

D;.;.;.

Eigen

Pathogenic

0.78

Eigen_PC

Pathogenic

0.70

FATHMM_MKL

Pathogenic

1.0

LIST_S2

Uncertain

0.95

D;D;D;D

M_CAP

Pathogenic

0.57

MetaRNN

Pathogenic

0.98

D;D;D;D

MetaSVM

Pathogenic

1.1

MutationAssessor

Uncertain

2.5

M;.;.;M

PrimateAI

Uncertain

0.54

PROVEAN

Pathogenic

-4.7

D;D;D;D

REVEL

Pathogenic

0.95

Sift

Uncertain

0.011

D;D;D;D

Sift4G

Uncertain

0.0090

D;D;D;D

Polyphen

1.0

D;.;.;.

Vest4

0.83

MutPred

0.79

Gain of phosphorylation at G137 (P = 0.0578);Gain of phosphorylation at G137 (P = 0.0578);.;Gain of phosphorylation at G137 (P = 0.0578);

MVP

1.0

MPC

0.78

ClinPred

0.98

GERP RS

5.4

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.8

Varity_R

0.60

gMVP

0.95

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.020

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