19-11111531-G-C

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 0P and 0B.

This summary comes from the ClinGen Evidence Repository: The NM_000527.5(LDLR):c.1078G>C (p.Asp360His) variant is classified as Uncertain significance - insufficient evidence for Familial Hypercholesterolemia by applying no ACMG/AMP evidence codes as defined by the ClinGen Familial Hypercholesterolemia Expert Panel LDLR-specific variant curation guidelines (specification version 1.2) on 28 October 2024. LINK:https://erepo.genome.network/evrepo/ui/classification/CA031936/MONDO:0007750/013

Frequency

Genomes: 𝑓 0.000039 ( 0 hom., cov: 31)
Exomes 𝑓: 0.000039 ( 2 hom. )

Consequence

LDLR
NM_000527.5 missense

Scores

1
5
13

Clinical Significance

Uncertain significance reviewed by expert panel U:7B:2

Conservation

PhyloP100: 0.547
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]

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 0 ACMG points.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
LDLRNM_000527.5 linkc.1078G>C p.Asp360His missense_variant Exon 8 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.1078G>C p.Asp360His missense_variant Exon 8 of 18 1 NM_000527.5 ENSP00000454071.1 P01130-1

Frequencies

GnomAD3 genomes
AF:
0.0000394
AC:
6
AN:
152188
Hom.:
0
Cov.:
31
show subpopulations
Gnomad AFR
AF:
0.00
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.000393
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.00
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.000163
AC:
41
AN:
251310
Hom.:
1
AF XY:
0.000110
AC XY:
15
AN XY:
135862
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.00110
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.00
Gnomad OTH exome
AF:
0.000489
GnomAD4 exome
AF:
0.0000390
AC:
57
AN:
1461448
Hom.:
2
Cov.:
31
AF XY:
0.0000330
AC XY:
24
AN XY:
727042
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.00112
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:
8.99e-7
Gnomad4 OTH exome
AF:
0.0000994
GnomAD4 genome
AF:
0.0000394
AC:
6
AN:
152188
Hom.:
0
Cov.:
31
AF XY:
0.0000403
AC XY:
3
AN XY:
74354
show subpopulations
Gnomad4 AFR
AF:
0.00
Gnomad4 AMR
AF:
0.000393
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.00
Gnomad4 OTH
AF:
0.00
Alfa
AF:
0.000214
Hom.:
0
Bravo
AF:
0.000162
ExAC
AF:
0.0000988
AC:
12

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:7Benign:2
Revision: reviewed by expert panel
LINK: link

Submissions by phenotype

Hypercholesterolemia, familial, 1 Uncertain:5
Uncertain significance, criteria provided, single submitterclinical testingIllumina Laboratory Services, IlluminaApr 18, 2019This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. -
Uncertain significance, criteria provided, single submitterresearchIberoamerican FH NetworkMar 01, 2016- -
Uncertain significance, reviewed by expert panelcurationClinGen Familial Hypercholesterolemia Variant Curation Expert PanelOct 28, 2024The NM_000527.5(LDLR):c.1078G>C (p.Asp360His) variant is classified as Uncertain significance - insufficient evidence for Familial Hypercholesterolemia by applying no ACMG/AMP evidence codes as defined by the ClinGen Familial Hypercholesterolemia Expert Panel LDLR-specific variant curation guidelines (specification version 1.2) on 28 October 2024. -
Uncertain significance, criteria provided, single submitterclinical testingCentogene AG - the Rare Disease CompanySep 04, 2020- -
Uncertain significance, criteria provided, single submitterclinical testingAll of Us Research Program, National Institutes of HealthSep 23, 2024This missense variant (also known as p.Asp339His in the mature protein) replaces aspartic acid with histidine at codon 360 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). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in over twenty heterozygous Hispanic individuals affected with hypercholesterolemia (PMID: 23064986, 29576406, 32113782) and in a homozygous individual affected with severe hypercholesterolemia and xanthoma (PMID: 29576406). However, this variant is common in the general population and has been identified in 43/282710 chromosomes (40/35438 Latino chromosomes; 0.1128%) by the Genome Aggregation Database (gnomAD). A study conducted in a Mexican population has reported that carriers of this variant show significantly higher LDL-C levels than non-carriers (PMID: 32113782). This study only looked for the presence of this variant in affected individuals and did not screen for other variants in the LDLR gene or other genes known to cause familial hypercholesterolemia. Therefore, it is not clear if this variant is responsible for the observed phenotype. 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. -
Familial hypercholesterolemia Uncertain:1Benign:1
Likely benign, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpDec 17, 2024- -
Uncertain significance, criteria provided, single submitterclinical testingColor Diagnostics, LLC DBA Color HealthFeb 01, 2023This missense variant (also known as p.Asp339His in the mature protein) replaces aspartic acid with histidine at codon 360 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). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in over twenty heterozygous Hispanic individuals affected with hypercholesterolemia (PMID: 23064986, 29576406, 32113782) and in a homozygous individual affected with severe hypercholesterolemia and xanthoma (PMID: 29576406). However, this variant is common in the general population and has been identified in 43/282710 chromosomes (40/35438 Latino chromosomes; 0.1128%) by the Genome Aggregation Database (gnomAD). A study conducted in a Mexican population has reported that carriers of this variant show significantly higher LDL-C levels than non-carriers (PMID: 32113782). This study only looked for the presence of this variant in affected individuals and did not screen for other variants in the LDLR gene or other genes known to cause familial hypercholesterolemia. Therefore, it is not clear if this variant is responsible for the observed phenotype. 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 specified Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingWomen's Health and Genetics/Laboratory Corporation of America, LabCorpNov 19, 2024Variant summary: LDLR c.1078G>C (p.Asp360His) results in a non-conservative amino acid change located in the EGF-like calcium-binding domain (IPR001881) of the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.00016 in 251310 control chromosomes, predominantly at a frequency of 0.0011 within the Latino subpopulation in the gnomAD database, including 1 homozygote. The observed variant frequency within Latino control individuals in the gnomAD database is approximately equal to the estimated maximal expected allele frequency for a pathogenic variant in LDLR causing Early Onset Coronary Artery Disease phenotype (0.001). c.1078G>C has been reported in the literature in individuals affected with hypercholesterolemia, including in a family with 1 homozygous and 4 heterozygous affected individuals (e.g., Ahmad_2012, Vasquez-Cardenas_2016 (no PMID), Hernandez-Flores_2018, Hernandez-Flores_2020). Additionally, one study suggested the variant may represent a founder mutation in an isolated Mexican community, however this could not be conclusively confirmed as the study only utilized targeted genotyping (e.g., Hernandez-Flores_2020). These reports therefore do not provide unequivocal conclusions about association of the variant with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 23064986, 32113782, 29576406). ClinVar contains an entry for this variant (Variation ID: 523715). Based on the evidence outlined above, the variant was classified as VUS-possibly benign. -
Cardiovascular phenotype Benign:1
Likely benign, criteria provided, single submitterclinical testingAmbry GeneticsJul 03, 2024This 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
0.13
BayesDel_addAF
Benign
-0.089
T
BayesDel_noAF
Uncertain
0.060
CADD
Benign
16
DANN
Benign
0.93
DEOGEN2
Uncertain
0.67
D;.;.;.;.;.
Eigen
Benign
-0.67
Eigen_PC
Benign
-0.56
FATHMM_MKL
Uncertain
0.96
D
LIST_S2
Benign
0.57
T;T;T;T;T;T
M_CAP
Pathogenic
0.60
D
MetaRNN
Benign
0.099
T;T;T;T;T;T
MetaSVM
Benign
-0.33
T
MutationAssessor
Benign
0.96
L;.;.;.;.;L
PrimateAI
Benign
0.29
T
PROVEAN
Benign
-1.5
N;N;N;N;N;N
REVEL
Uncertain
0.55
Sift
Benign
0.047
D;D;T;D;T;D
Sift4G
Uncertain
0.056
T;D;D;T;D;T
Polyphen
0.0010
B;.;.;.;.;.
Vest4
0.11
MutPred
0.54
Gain of catalytic residue at D360 (P = 0.0452);Gain of catalytic residue at D360 (P = 0.0452);.;.;.;Gain of catalytic residue at D360 (P = 0.0452);
MVP
1.0
MPC
0.26
ClinPred
0.037
T
GERP RS
0.44
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.7
Varity_R
0.32
gMVP
0.88

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: rs777926251; hg19: chr19-11222207; API