rs730882107

Variant names:

• chr19-11113756-T-C
• rs730882107
• NM_000527.5:c.1580T>C

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 3P and 3B. PM1 PP2 BP4_Moderate BP6

The NM_000527.5(LDLR):​c.1580T>C​(p.Val527Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000158 in 1,460,142 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/22 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. V527I) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.000016 (0 hom.)
• Consequence: LDLR NM_000527.5 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:5 B:2 O:1
• Conservation: PhyloP100: 0.198
• Publications: 1 publications found

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]

MIR6886 (HGNC:50121): (microRNA 6886) microRNAs (miRNAs) are short (20-24 nt) non-coding RNAs that are involved in post-transcriptional regulation of gene expression in multicellular organisms by affecting both the stability and translation of mRNAs. miRNAs are transcribed by RNA polymerase II as part of capped and polyadenylated primary transcripts (pri-miRNAs) that can be either protein-coding or non-coding. The primary transcript is cleaved by the Drosha ribonuclease III enzyme to produce an approximately 70-nt stem-loop precursor miRNA (pre-miRNA), which is further cleaved by the cytoplasmic Dicer ribonuclease to generate the mature miRNA and antisense miRNA star (miRNA*) products. The mature miRNA is incorporated into a RNA-induced silencing complex (RISC), which recognizes target mRNAs through imperfect base pairing with the miRNA and most commonly results in translational inhibition or destabilization of the target mRNA. The RefSeq represents the predicted microRNA stem-loop. [provided by RefSeq, Sep 2009]

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM1: In a hotspot region, there are 21 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 27 uncertain in NM_000527.5
• PP2: Missense variant in the gene, where a lot of missense mutations are associated with disease in ClinVar. The gene has 678 curated pathogenic missense variants (we use a threshold of 10). The gene has 92 curated benign missense variants. Gene score misZ: 0.12407 (below the threshold of 3.09). Trascript score misZ: 0.59338 (below the threshold of 3.09). GenCC associations: The gene is linked to hypercholesterolemia, familial, 1, homozygous familial hypercholesterolemia.
• BP4: Computational evidence support a benign effect (MetaRNN=0.1515767).
• BP6: Variant 19-11113756-T-C is Benign according to our data. Variant chr19-11113756-T-C is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 183121.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
LDLR	NM_000527.5	c.1580T>C	p.Val527Ala	missense_variant	Exon 10 of 18	ENST00000558518.6	NP_000518.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
LDLR	ENST00000558518.6	c.1580T>C	p.Val527Ala	missense_variant	Exon 10 of 18	1	NM_000527.5	ENSP00000454071.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.0000756 AC: 19 AN: 251244 AF XY: 0.0000810

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000376

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000440

Gnomad OTH exome AF: 0.000163

GnomAD4 exome AF: 0.0000158 AC: 23 AN: 1460142 Hom.: 0 Cov.: 34 AF XY: 0.0000179 AC XY: 13 AN XY: 726512

African (AFR) AF: 0.00 AC: 0 AN: 33438

American (AMR) AF: 0.000291 AC: 13 AN: 44716

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26124

East Asian (EAS) AF: 0.00 AC: 0 AN: 39692

South Asian (SAS) AF: 0.00 AC: 0 AN: 86204

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53406

Middle Eastern (MID) AF: 0.000174 AC: 1 AN: 5762

European-Non Finnish (NFE) AF: 0.00000720 AC: 8 AN: 1110480

Other (OTH) AF: 0.0000166 AC: 1 AN: 60320

GnomAD4 genome Cov.: 32

Alfa AF: 0.0000986 Hom.: 0

Bravo AF: 0.0000227

ExAC AF: 0.0000576 AC: 7

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:5 Benign:2 Other:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Hypercholesterolemia, familial, 1 Uncertain:2

Jun 09, 2024

All of Us Research Program, National Institutes of Health

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This missense variant (also known as p.Val506Ala in the mature protein) replaces valine with alanine at codon 527 of the LDLR protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). A functional study has shown that this variant does not disrupt LDLR protein function (PMID: 25647241). To our knowledge, this variant has not been reported in individuals affected with familial hypercholesterolemia in the literature. This variant has been identified in 19/251244 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The 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. -

Nov 16, 2021

Fulgent Genetics, Fulgent Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Familial hypercholesterolemia Uncertain:1 Benign:1

Apr 15, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

May 27, 2024

Color Diagnostics, LLC DBA Color Health

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This missense variant replaces valine with alanine at codon 527 of the LDLR protein. This variant is also known as p.Val506Ala in the mature protein. Computational prediction tools indicate that this variant's impact on protein structure and function is inconclusive. A functional study has shown that this variant does not disrupt LDLR protein function (PMID: 25647241). To our knowledge, this variant has not been reported in individuals affected with LDLR-related disorders in the literature. This variant has been identified in 19/251244 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The 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. -

not provided Uncertain:1 Other:1

-

Dept. of Genetics and Pharmacogenomics, Merck Research Labs

Significance: not provided

Review Status: no classification provided

Collection Method: in vitro

- -

Aug 02, 2019

GeneDx

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 25647241) -

not specified Uncertain:1

Jun 23, 2025

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

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: LDLR c.1580T>C (p.Val527Ala) results in a non-conservative amino acid change in the encoded protein sequence. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change. The variant allele was found at a frequency of 7.6e-05 in 251244 control chromosomes. This frequency is not significantly higher than estimated for a pathogenic variant in LDLR causing Familial Hypercholesterolemia (7.6e-05 vs 0.0013), allowing no conclusion about variant significance. To our knowledge, no occurrence of c.1580T>C in individuals affected with Familial Hypercholesterolemia has been reported. At least one publication reports experimental evidence evaluating an impact on protein function. These results showed no damaging effect of this variant (Thormaehlen_2015). The following publication has been ascertained in the context of this evaluation (PMID: 25647241). ClinVar contains an entry for this variant (Variation ID: 183121). Based on the evidence outlined above, the variant was classified as uncertain significance. -

Cardiovascular phenotype Benign:1

Apr 04, 2025

Ambry Genetics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.054	T
BayesDel_noAF	Uncertain	0.010
CADD	Benign	15
DANN	Benign	0.88
DEOGEN2	Uncertain	0.76	D;.;.;.;.;.
Eigen	Benign	-1.0
Eigen_PC	Benign	-1.0
FATHMM_MKL	Benign	0.37	N
LIST_S2	Benign	0.68	T;T;T;T;T;T
M_CAP	Uncertain	0.17	D
MetaRNN	Benign	0.15	T;T;T;T;T;T
MetaSVM	Benign	-0.64	T
MutationAssessor	Benign	0.56	N;.;.;.;.;N
PhyloP100		0.20
PrimateAI	Benign	0.30	T
PROVEAN	Benign	-1.9	N;N;N;N;N;N
REVEL	Uncertain	0.56
Sift	Benign	0.075	T;T;D;T;T;T
Sift4G	Benign	0.093	T;T;T;T;T;T
Polyphen		0.0	B;.;.;.;.;.
Vest4		0.12
MVP		1.0
MPC		0.26
ClinPred		0.014	T
GERP RS		1.3
RBP_binding_hub_radar		0.97
RBP_regulation_power_radar		2.1
Varity_R		0.25
gMVP		0.94
Mutation Taster		=46/54	disease causing

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

Other links and lift over

dbSNP: rs730882107; hg19: chr19-11224432;