19-11107506-A-G

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM1 PM2 PM5

The NM_000527.5(LDLR):c.932A>G(p.Lys311Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000412 in 1,456,162 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. K311T) has been classified as Likely pathogenic.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000041 (0 hom.)
• Consequence: LDLR NM_000527.5 missense
• Clinical Significance: Uncertain significance reviewed by expert panel P:2 U:4 B:1
• Conservation: PhyloP100: 2.56

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 Likely_pathogenic. Variant got 6 ACMG points.

• PM1: In a hotspot region, there are 11 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 9 uncertain 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 chr19-11107506-A-C is described in ClinVar as [Uncertain_significance]. Clinvar id is 251531.Status of the report is reviewed_by_expert_panel, 3 stars. We mark this variant Likely_pathogenic, oryginal submissions are: {Likely_pathogenic=2, Uncertain_significance=3}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
LDLR	NM_000527.5	c.932A>G	p.Lys311Arg	missense_variant	6/18	ENST00000558518.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
LDLR	ENST00000558518.6	c.932A>G	p.Lys311Arg	missense_variant	6/18	1	NM_000527.5	P3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000412 AC: 6 AN: 1456162 Hom.: 0 Cov.: 32 AF XY: 0.00000690 AC XY: 5 AN XY: 724384

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: 0.00000451

Gnomad4 OTH exome AF: 0.0000167

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Pathogenic:2 Uncertain:4 Benign:1

Revision: reviewed by expert panel

Submissions by phenotype

Hypercholesterolemia, familial, 1 Pathogenic:2 Uncertain:1 Benign:1

Likely benign, criteria provided, single submitter	literature only	LDLR-LOVD, British Heart Foundation	Mar 25, 2016	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Centre de Génétique Moléculaire et Chromosomique, Unité de génétique de l'Obésité et des Dyslipidémies, APHP, GH Hôpitaux Universitaires Pitié-Salpêtrière / Charles-Foix	Dec 16, 2016	subjects mutated among 2600 FH index cases screened = 3 , family members = 2 with co-segregation c.932A>G, c.939C>G / p.Lys311Arg, p.Cys313Trp systematicaly associated (Van Leuven et al. Atherosclerosis 2001) / Software predictions: Conflicting -
Uncertain significance, reviewed by expert panel	curation	ClinGen Familial Hypercholesterolemia Variant Curation Expert Panel	Jan 17, 2022	The NM_000527.5(LDLR):c.932A>G (p.Lys311Arg) variant is classified as Uncertain significance - insufficient evidence for Familial Hypercholesterolemia by applying evidence codes (PM2, PM3 and PP4) 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 - This variant is absent from gnomAD (gnomAD v2.1.1), so PM2 is Met. PM3 - Variant meets PM2 and is identified in an index case with homozygous FH phenotype (plasma cholesterol > 600mg/dL) and LDLR variant NM_000527.5(LDLR):c.910G>T (p.Asp304Tyr) (ClinVar ID: 251517), classified as Likely pathogenic by these guidelines, in trans (PMID: 1301940), so PM3 is Met. PP4 - Variant meets PM2 and is identified in 1 index-case with SB/DLCN score of definite FH (plasma cholesterol > 600mg/dL with tendon xanthomas) from France (PMID: 1301940), so PP4 is Met. -
Pathogenic, no assertion criteria provided	research	Laboratorium voor Moleculaire Diagnostiek Experimentele Vasculaire Geneeskunde, Academisch Medisch Centrum	-	- -

Familial hypercholesterolemia Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Invitae	Nov 25, 2023	This sequence change replaces lysine, which is basic and polar, with arginine, which is basic and polar, at codon 311 of the LDLR protein (p.Lys311Arg). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with hypercholesterolemia (PMID: 1301940, 11810272, 15523646, 20506408, 32331935). This variant is also known as K290R. ClinVar contains an entry for this variant (Variation ID: 251532). 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) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on LDLR protein function. 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. -
Uncertain significance, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	May 30, 2019	This missense variant (also known as p.Lys290Arg in the mature protein) replaces lysine with arginine at codon 311 of the LDLR protein. Computational prediction tools and conservation analyses are inconclusive regarding the impact of this variant on the protein function. Computational splicing tools suggest that this variant may not impact RNA splicing. To our knowledge, functional assays have not been performed for this variant. This variant has been reported in individuals affected with hypercholesterolemia (PMID: 1301940, 15523646, 20506408). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). 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. -

Cardiovascular phenotype Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jun 27, 2022

The p.K311R variant (also known as c.932A>G), located in coding exon 6 of the LDLR gene, results from an A to G substitution at nucleotide position 932. The lysine at codon 311 is replaced by arginine, an amino acid with highly similar properties. This variant (also referred to as K290R) has been detected in individuals reported to have FH or from FH cohorts, and has been detected with the LDLR p.C313W variant (Descamps OS et al. Atherosclerosis, 2001 Aug;157:514-8; Fouchier SW et al. Hum Genet, 2001 Dec;109:602-15; Van Leuven F et al. Atherosclerosis. 2001 Feb;154(3):567-77; Amsellem S et al. Hum Genet, 2002 Dec;111:501-10; van der Graaf A et al. Circulation, 2011 Mar;123:1167-73Tada H et al. J Clin Lipidol Mar;14:346-351.e9). This variant co-occurred in trans with another variant in the LDLR gene in an individual with clinical homozygous FH presentation (Loux N et al. Hum Mutat, 1992;1:325-32). This amino acid position is not well conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.086
BayesDel_addAF	Pathogenic	0.26	D
BayesDel_noAF	Uncertain	0.13
Cadd	Benign	16
Dann	Uncertain	0.99
DEOGEN2	Uncertain	0.66	D;.;.;.;.;.
Eigen	Benign	-0.36
Eigen_PC	Benign	-0.23
FATHMM_MKL	Uncertain	0.87	D
LIST_S2	Benign	0.83	T;T;T;T;T;T
M_CAP	Pathogenic	0.30	D
MetaRNN	Uncertain	0.54	D;D;D;D;D;D
MetaSVM	Uncertain	0.16	D
MutationAssessor	Benign	0.93	L;.;.;.;.;L
MutationTaster	Benign	1.0	D;D;D;D;D;D;D
PrimateAI	Benign	0.36	T
PROVEAN	Benign	-1.8	N;N;N;N;N;N
Sift	Benign	0.12	T;T;T;T;T;T
Sift4G	Benign	0.23	T;T;T;T;T;T
Polyphen		0.0010	B;.;.;.;.;.
Vest4		0.23
MutPred		0.84		Loss of ubiquitination at K311 (P = 0.013);Loss of ubiquitination at K311 (P = 0.013);.;.;.;Loss of ubiquitination at K311 (P = 0.013);
MVP		1.0
MPC		0.19
ClinPred		0.64	D
GERP RS		4.3
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.32
gMVP		0.81

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

Other links and lift over

dbSNP: rs761765254; hg19: chr19-11218182;