chr19-11113315-G-C
Variant summary
Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. BP4PM2
This summary comes from the ClinGen Evidence Repository: The NM_000527.5(LDLR):c.1224G>C (p.Glu408Asp) variant is classified as Uncertain significance - insufficient evidence for Familial Hypercholesterolemia by applying evidence PM2 and BP4 as defined by the ClinGen Familial Hypercholesterolemia Expert Panel LDLR-specific variant curation guidelines (https://doi.org/10.1101/2021.03.17.21252755). The supporting evidence is as follows:PM2 - This variant was not identified in gnomAD (gnomAD v2.1.1), so PM2 is met.BP4 - REVEL = 0.414. It is below 0.50, splicing evaluation required.Functional data on splicing not available.A) not on limitsB) does not create AGVariant is not predicted to alter splicing, so BP4 is met LINK:https://erepo.genome.network/evrepo/ui/classification/CA305300066/MONDO:0007750/013
Frequency
Consequence
NM_000527.5 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Uncertain_significance. Variant got 1 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
LDLR | NM_000527.5 | c.1224G>C | p.Glu408Asp | missense_variant | 9/18 | ENST00000558518.6 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
LDLR | ENST00000558518.6 | c.1224G>C | p.Glu408Asp | missense_variant | 9/18 | 1 | NM_000527.5 | P3 |
Frequencies
GnomAD3 genomes Cov.: 29
GnomAD4 exome AF: 6.84e-7 AC: 1AN: 1461486Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0AN XY: 727062
GnomAD4 genome Cov.: 29
ClinVar
Submissions by phenotype
Hypercholesterolemia, familial, 1 Uncertain:2
Uncertain significance, reviewed by expert panel | curation | ClinGen Familial Hypercholesterolemia Variant Curation Expert Panel | Dec 16, 2021 | The NM_000527.5(LDLR):c.1224G>C (p.Glu408Asp) variant is classified as Uncertain significance - insufficient evidence for Familial Hypercholesterolemia by applying evidence PM2 and BP4 as defined by the ClinGen Familial Hypercholesterolemia Expert Panel LDLR-specific variant curation guidelines (https://doi.org/10.1101/2021.03.17.21252755). The supporting evidence is as follows: PM2 - This variant was not identified in gnomAD (gnomAD v2.1.1), so PM2 is met. BP4 - REVEL = 0.414. It is below 0.50, splicing evaluation required. Functional data on splicing not available. A) not on limits B) does not create AG Variant is not predicted to alter splicing, so BP4 is met - |
Uncertain significance, criteria provided, single submitter | research | Laboratory of Genetics and Molecular Cardiology, University of São Paulo | Mar 01, 2016 | - - |
not specified Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Apr 09, 2024 | Variant summary: LDLR c.1224G>C (p.Glu408Asp) results in a conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant was absent in 251128 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.1224G>C has been reported in the literature in an individual affected with high LDL cholesterol, without strong evidence for causality (Lange_2014). This report does not provide unequivocal conclusions about association of the variant with Familial Hypercholesterolemia. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publication have been ascertained in the context of this evaluation (PMID: 24507775). ClinVar contains an entry for this variant (Variation ID: 431524). Based on the evidence outlined above, the variant was classified as uncertain significance. - |
Cardiovascular phenotype Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Mar 08, 2021 | The p.E408D variant (also known as c.1224G>C), located in coding exon 9 of the LDLR gene, results from a G to C substitution at nucleotide position 1224. The glutamic acid at codon 408 is replaced by aspartic acid, an amino acid with highly similar properties. This variant was detected in an individual of European ancestry with high LDL-C in an exome cohort; however, clinical details were limited (Lange LA et al. Am J Hum Genet, 2014 Feb;94:233-45). This amino acid position is well conserved in available vertebrate species; however, aspartic acid is the reference amino acid in other 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:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at