rs730882082

Variant names:

• chr19-11105315-G-A
• rs730882082
• NM_000527.5:c.409G>A

Your query was ambiguous. Multiple possible variants found:

• chr19-11105315-G-A
• chr19-11105315-G-T

Variant summary

Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PM1 PM2 PM5 PP3_Strong PP5

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
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:8 U:1 O:1
• Conservation: PhyloP100: 9.88

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]

ACMG classification

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: {Likely_pathogenic=5, Uncertain_significance=1, Pathogenic=1, not_provided=1}. Variant chr19-11105315-G-A is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
LDLR	NM_000527.5	c.409G>A	p.Gly137Ser	missense_variant	Exon 4 of 18	ENST00000558518.6	NP_000518.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
LDLR	ENST00000558518.6	c.409G>A	p.Gly137Ser	missense_variant	Exon 4 of 18	1	NM_000527.5	ENSP00000454071.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD3 exomes AF: 0.0000159 AC: 4 AN: 251184 Hom.: 0 AF XY: 0.0000221 AC XY: 3 AN XY: 135852

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: 17 AN: 1461528 Hom.: 1 Cov.: 33 AF XY: 0.00000963 AC XY: 7 AN XY: 727104

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.: 33

ExAC AF: 0.00000824 AC: 1

EpiCase AF: 0.00

EpiControl AF: 0.0000593

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:8 Uncertain:1 Other:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Hypercholesterolemia, familial, 1 Pathogenic:3

Mar 25, 2016

LDLR-LOVD, British Heart Foundation

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: literature only

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Nov 05, 2016

Molecular Genetics Laboratory, Centre for Cardiovascular Surgery and Transplantation

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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Laboratorium voor Moleculaire Diagnostiek Experimentele Vasculaire Geneeskunde, Academisch Medisch Centrum

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: research

- -

not provided Pathogenic:1 Uncertain:1 Other:1

Jun 20, 2024

GeneDx

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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) -

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Dept. of Genetics and Pharmacogenomics, Merck Research Labs

Significance: not provided

Review Status: no classification provided

Collection Method: in vitro

- -

Dec 01, 2019

CeGaT Center for Human Genetics Tuebingen

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Familial hypercholesterolemia Pathogenic:2

Oct 30, 2023

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.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. -

May 22, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces glycine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 137 of the LDLR protein (p.Gly137Ser). This variant is present in population databases (rs730882082, gnomAD 0.003%). This missense change has been observed in individuals with hypercholesterolemia (PMID: 15823288, 25414273, 25487149, 33740630, 36267056). It is commonly reported in individuals of Arctic Inuit/Greenlander ancestry (PMID: 25414273, 36267056). This variant is also known as G116S. ClinVar contains an entry for this variant (Variation ID: 183087). 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%. Experimental studies have shown that this missense change affects LDLR function (PMID: 25414273). In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. -

LDLR-related disorder Pathogenic:1

Jun 13, 2024

PreventionGenetics, part of Exact Sciences

Significance: Likely pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

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

Aug 15, 2023

Ambry Genetics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.16
BayesDel_addAF	Pathogenic	0.46	D
BayesDel_noAF	Pathogenic	0.52
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.88	D;.;.;.
Eigen	Pathogenic	0.78
Eigen_PC	Pathogenic	0.70
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Uncertain	0.95	D;D;D;D
M_CAP	Pathogenic	0.57	D
MetaRNN	Pathogenic	0.98	D;D;D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Uncertain	2.5	M;.;.;M
PrimateAI	Uncertain	0.54	T
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	D
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

Other links and lift over

dbSNP: rs730882082; hg19: chr19-11215991;