rs373848925

chr19-11113692-G-Achr19-11113692-G-C

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 4P and 3B. PM1 PM2 BP4_Moderate BP6

The NM_000527.5(LDLR):c.1516G>A(p.Val506Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000279 in 1,614,062 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign 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. V506L) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.000099 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000021 (0 hom.)
• Consequence: LDLR NM_000527.5 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1 U:4 B:2
• Conservation: PhyloP100: -0.553

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 Uncertain_significance. Variant got 1 ACMG points.

• PM1: In a hotspot region, there are 6 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 2 benign, 11 uncertain in NM_000527.5
• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.20849743).
• BP6: Variant 19-11113692-G-A is Benign according to our data. Variant chr19-11113692-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 251881.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=4, Likely_benign=2}. Variant chr19-11113692-G-A is described in Lovd as [Likely_benign].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
LDLR	NM_000527.5	c.1516G>A	p.Val506Met	missense_variant	10/18	ENST00000558518.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
LDLR	ENST00000558518.6	c.1516G>A	p.Val506Met	missense_variant	10/18	1	NM_000527.5	P3

Frequencies

GnomAD3 genomes AF: 0.0000986 AC: 15 AN: 152190 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000724

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000524

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000385

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000294

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000636 AC: 16 AN: 251450 Hom.: 0 AF XY: 0.0000809 AC XY: 11 AN XY: 135908

Gnomad AFR exome AF: 0.0000615

Gnomad AMR exome AF: 0.0000289

Gnomad ASJ exome AF: 0.0000992

Gnomad EAS exome AF: 0.000707

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000205 AC: 30 AN: 1461872 Hom.: 0 Cov.: 35 AF XY: 0.0000206 AC XY: 15 AN XY: 727246

Gnomad4 AFR exome AF: 0.0000299

Gnomad4 AMR exome AF: 0.0000224

Gnomad4 ASJ exome AF: 0.0000383

Gnomad4 EAS exome AF: 0.000403

Gnomad4 SAS exome AF: 0.0000116

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000719

Gnomad4 OTH exome AF: 0.0000331

GnomAD4 genome AF: 0.0000986 AC: 15 AN: 152190 Hom.: 0 Cov.: 32 AF XY: 0.000121 AC XY: 9 AN XY: 74348

Gnomad4 AFR AF: 0.0000724

Gnomad4 AMR AF: 0.000524

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000385

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000294

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0000644 Hom.: 0

Bravo AF: 0.000102

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.0000824 AC: 10

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

Significance: Conflicting classifications of pathogenicity

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

Revision: criteria provided, conflicting classifications

Submissions by phenotype

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

Uncertain significance, criteria provided, single submitter	clinical testing	All of Us Research Program, National Institutes of Health	Jan 11, 2024	This missense variant (also known as p.Val485Met in the mature protein) replaces valine with methionine at codon 506 of the LDLR protein. Computational prediction suggests that this variant may have a deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). To our knowledge, functional studies have not been performed for this variant. This variant has been reported in an individual affected with familial hypercholesterolemia, who also carried a large duplication variant encompassing LDLR exons 3-12 (PMID: 20145306). This variant has also been reported in another individual affected with familial hypercholesterolemia (PMID: 32770674) and in an individual affected with early-onset myocardial infarction (PMID: 25487149). This variant has been identified in 16/251450 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The elevated variant allele frequency in the general population indicates that this variant may not be disease-causing. However, additional studies are necessary to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. -
Likely benign, criteria provided, single submitter	literature only	LDLR-LOVD, British Heart Foundation	Mar 25, 2016	- -
Pathogenic, no assertion criteria provided	research	Laboratorium voor Moleculaire Diagnostiek Experimentele Vasculaire Geneeskunde, Academisch Medisch Centrum	-	- -

Familial hypercholesterolemia Uncertain:1 Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Apr 24, 2023	This missense variant (also known as p.Val485Met in the mature protein) replaces valine with methionine at codon 506 of the LDLR protein. Computational prediction suggests that this variant may have a deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). To our knowledge, functional studies have not been performed for this variant. This variant has been reported in an individual affected with familial hypercholesterolemia, who also carried a large duplication variant encompassing LDLR exons 3-12 (PMID: 20145306). This variant has also been reported in another individual affected with familial hypercholesterolemia (PMID: 32770674) and in an individual affected with early-onset myocardial infarction (PMID: 25487149). This variant has been identified in 16/251450 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The elevated variant allele frequency in the general population indicates that this variant may not be disease-causing. However, additional studies are necessary to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. -
Likely benign, criteria provided, single submitter	clinical testing	Invitae	Jan 04, 2024	- -

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Jan 11, 2021

- -

Cardiovascular phenotype Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jul 18, 2018

The p.V506M variant (also known as c.1516G>A), located in coding exon 10 of the LDLR gene, results from a G to A substitution at nucleotide position 1516. The valine at codon 506 is replaced by methionine, an amino acid with highly similar properties. This variant has been reported in one individual from an early myocardial infarction cohort, as well as in an individual with familial hypercholesterolemia (FH), who had an additional LDLR variant; however, clinical details were limited in both cases (Chmara M et al. J. Appl. Genet., 2010;51:95-106; Do R et al. Nature, 2015 Feb;518:102-6). Based on data from gnomAD, the A allele has an overall frequency of approximately 0.007% (17/246252) total alleles studied. The highest observed frequency was 0.075% (13/17248) of East Asian alleles. This amino acid position is poorly conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated 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	0.088
BayesDel_addAF	Benign	-0.29	T
BayesDel_noAF	Benign	-0.28
Cadd	Benign	1.0
Dann	Benign	0.93
DEOGEN2	Uncertain	0.51	D;.;.;.;.;.
Eigen	Benign	-1.2
Eigen_PC	Benign	-1.3
FATHMM_MKL	Benign	0.24	N
LIST_S2	Benign	0.29	T;T;T;T;T;T
M_CAP	Uncertain	0.15	D
MetaRNN	Benign	0.21	T;T;T;T;T;T
MetaSVM	Uncertain	-0.20	T
MutationAssessor	Benign	0.69	N;.;.;.;.;N
MutationTaster	Benign	1.0	N;N;N;N;N;N;N
PrimateAI	Benign	0.28	T
PROVEAN	Benign	-0.41	N;N;N;N;N;N
Sift	Benign	0.12	T;T;T;T;T;T
Sift4G	Benign	0.21	T;T;T;T;T;T
Polyphen		0.57	P;.;.;.;.;.
Vest4		0.30
MVP		0.97
MPC		0.24
ClinPred		0.047	T
GERP RS		-7.3
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.12
gMVP		0.84

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: rs373848925; hg19: chr19-11224368; COSMIC: COSV52942560; COSMIC: COSV52942560;