19-11131312-C-T

Variant summary

Our verdict is Benign. Variant got -10 ACMG points: 0P and 10B. BP4_StrongBP6BS1BS2_Supporting

The NM_000527.5(LDLR):​c.2579C>T​(p.Ala860Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000164 in 1,614,126 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.000098 ( 0 hom., cov: 32)
Exomes 𝑓: 0.00017 ( 2 hom. )

Consequence

LDLR
NM_000527.5 missense

Scores

2
7
10

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3B:3

Conservation

PhyloP100: 1.51
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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -10 ACMG points.

BP4
Computational evidence support a benign effect (MetaRNN=0.058515072).
BP6
Variant 19-11131312-C-T is Benign according to our data. Variant chr19-11131312-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 374957.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=2, Benign=1, Likely_benign=2}.
BS1
Variant frequency is greater than expected in population eas. gnomad4_exome allele frequency = 0.000171 (250/1461826) while in subpopulation EAS AF= 0.00486 (193/39698). AF 95% confidence interval is 0.0043. There are 2 homozygotes in gnomad4_exome. There are 106 alleles in male gnomad4_exome subpopulation. Median coverage is 34. This position pass quality control queck.
BS2
High Homozygotes in GnomAdExome4 at 2 SD geneVariant has number of homozygotes lower than other variant known as pathogenic in the gene, so the strength is limited to Supporting.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
LDLRNM_000527.5 linkc.2579C>T p.Ala860Val missense_variant Exon 18 of 18 ENST00000558518.6 NP_000518.1 P01130-1A0A024R7D5

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
LDLRENST00000558518.6 linkc.2579C>T p.Ala860Val missense_variant Exon 18 of 18 1 NM_000527.5 ENSP00000454071.1 P01130-1

Frequencies

GnomAD3 genomes
AF:
0.0000986
AC:
15
AN:
152182
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.0000241
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00231
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:
0.0000517
AC:
13
AN:
251488
Hom.:
0
AF XY:
0.0000515
AC XY:
7
AN XY:
135918
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.0000578
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.000489
Gnomad SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.0000176
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.000171
AC:
250
AN:
1461826
Hom.:
2
Cov.:
34
AF XY:
0.000146
AC XY:
106
AN XY:
727222
show subpopulations
Gnomad4 AFR exome
AF:
0.0000299
Gnomad4 AMR exome
AF:
0.0000447
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00486
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.0000441
Gnomad4 OTH exome
AF:
0.0000828
GnomAD4 genome
AF:
0.0000985
AC:
15
AN:
152300
Hom.:
0
Cov.:
32
AF XY:
0.000134
AC XY:
10
AN XY:
74464
show subpopulations
Gnomad4 AFR
AF:
0.0000241
Gnomad4 AMR
AF:
0.00
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00231
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.0000294
Gnomad4 OTH
AF:
0.00
Alfa
AF:
0.0000524
Hom.:
0
Bravo
AF:
0.0000491
TwinsUK
AF:
0.00
AC:
0
ALSPAC
AF:
0.000259
AC:
1
ExAC
AF:
0.0000659
AC:
8
Asia WGS
AF:
0.000289
AC:
1
AN:
3478

ClinVar

Significance: Conflicting classifications of pathogenicity
Submissions summary: Uncertain:3Benign:3
Revision: criteria provided, conflicting classifications
LINK: link

Submissions by phenotype

Familial hypercholesterolemia Benign:3
Likely benign, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpDec 02, 2024- -
Benign, criteria provided, single submitterclinical testingDepartment of Molecular Innovation in Lipidology, National Cerebral & Cardiovascular Center Reseach InstituteNov 20, 2018LDLR A860V variant is interpreted as a benign variant based on pedigree-based genetic analysis. -
Likely benign, criteria provided, single submitterclinical testingColor Diagnostics, LLC DBA Color HealthMay 07, 2019- -
Hypercholesterolemia, familial, 1 Uncertain:2
Uncertain significance, criteria provided, single submitterclinical testingRobarts Research Institute, Western UniversityJan 02, 2018- -
Uncertain significance, no assertion criteria providedclinical testingKnight Diagnostic Laboratories, Oregon Health and Sciences UniversityMar 30, 2016- -
not provided Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingGeneDxMar 12, 2025Observed in individuals with familial hypercholesterolemia (PMID: 18718593, 34176852, 35480308); Segregation studies in two families with the p.(A860V) and another LDLR variant, suggest that the p.(A860V) is likely not segregating with the disease in these families (Hori et al., 2019); these findings suggest that p.(A860V) is a benign variant (PMID: 30745271); In silico analysis indicates that this missense variant does not alter protein structure/function; Also known as p.(A839V); This variant is associated with the following publications: (PMID: 26332594, 25487149, 34176852, 18718593, 33020668, 31491741, 35480308, 30745271) -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.084
BayesDel_addAF
Benign
-0.0028
T
BayesDel_noAF
Uncertain
0.10
CADD
Benign
20
DANN
Uncertain
0.99
DEOGEN2
Uncertain
0.51
D;.;.;.;.
Eigen
Benign
-0.19
Eigen_PC
Benign
-0.29
FATHMM_MKL
Benign
0.54
D
LIST_S2
Uncertain
0.86
D;D;D;T;D
M_CAP
Pathogenic
0.38
D
MetaRNN
Benign
0.059
T;T;T;T;T
MetaSVM
Uncertain
0.11
D
MutationAssessor
Uncertain
2.1
M;.;.;.;.
PrimateAI
Benign
0.45
T
PROVEAN
Benign
-1.4
N;N;N;N;N
REVEL
Pathogenic
0.66
Sift
Benign
0.032
D;D;D;D;D
Sift4G
Uncertain
0.0060
D;D;D;D;D
Polyphen
0.35
B;.;.;.;.
Vest4
0.16
MVP
1.0
MPC
0.24
ClinPred
0.13
T
GERP RS
2.6
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.1
Varity_R
0.13
gMVP
0.82

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

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs13306505; hg19: chr19-11241988; COSMIC: COSV99369624; COSMIC: COSV99369624; API