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
Consequence
NM_000527.5 missense
Scores
Clinical Significance
Conservation
Genome browser will be placed here
ACMG classification
Verdict is Uncertain_significance. Variant got 0 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
LDLR | NM_000527.5 | c.1078G>C | p.Asp360His | missense_variant | Exon 8 of 18 | ENST00000558518.6 | NP_000518.1 |
Ensembl
Frequencies
GnomAD3 genomes AF: 0.0000394 AC: 6AN: 152188Hom.: 0 Cov.: 31
GnomAD3 exomes AF: 0.000163 AC: 41AN: 251310Hom.: 1 AF XY: 0.000110 AC XY: 15AN XY: 135862
GnomAD4 exome AF: 0.0000390 AC: 57AN: 1461448Hom.: 2 Cov.: 31 AF XY: 0.0000330 AC XY: 24AN XY: 727042
GnomAD4 genome AF: 0.0000394 AC: 6AN: 152188Hom.: 0 Cov.: 31 AF XY: 0.0000403 AC XY: 3AN XY: 74354
ClinVar
Submissions by phenotype
Hypercholesterolemia, familial, 1 Uncertain:5
Uncertain significance, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Apr 18, 2019 | This 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 submitter | research | Iberoamerican FH Network | Mar 01, 2016 | - - |
Uncertain significance, reviewed by expert panel | curation | ClinGen Familial Hypercholesterolemia Variant Curation Expert Panel | Oct 28, 2024 | 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. - |
Uncertain significance, criteria provided, single submitter | clinical testing | Centogene AG - the Rare Disease Company | Sep 04, 2020 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | All of Us Research Program, National Institutes of Health | Sep 23, 2024 | This 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 submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Dec 17, 2024 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Color Diagnostics, LLC DBA Color Health | Feb 01, 2023 | This 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 submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Nov 19, 2024 | Variant 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 submitter | clinical testing | Ambry Genetics | Jul 03, 2024 | 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:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at