rs730882100
Variant summary
Our verdict is Likely pathogenic. Variant got 9 ACMG points: 9P and 0B. PM1PM2PM5PP3_ModeratePP5
The NM_000527.5(LDLR):āc.1294C>Gā(p.Leu432Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000744 in 1,613,868 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic 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. L432P) has been classified as Likely pathogenic.
Frequency
Consequence
NM_000527.5 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_pathogenic. Variant got 9 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
LDLR | NM_000527.5 | c.1294C>G | p.Leu432Val | missense_variant | 9/18 | ENST00000558518.6 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
LDLR | ENST00000558518.6 | c.1294C>G | p.Leu432Val | missense_variant | 9/18 | 1 | NM_000527.5 | P3 |
Frequencies
GnomAD3 genomes ? AF: 0.00000657 AC: 1AN: 152174Hom.: 0 Cov.: 29
GnomAD3 exomes AF: 0.0000159 AC: 4AN: 251290Hom.: 0 AF XY: 0.0000294 AC XY: 4AN XY: 135890
GnomAD4 exome AF: 0.00000753 AC: 11AN: 1461694Hom.: 0 Cov.: 32 AF XY: 0.0000138 AC XY: 10AN XY: 727158
GnomAD4 genome ? AF: 0.00000657 AC: 1AN: 152174Hom.: 0 Cov.: 29 AF XY: 0.0000135 AC XY: 1AN XY: 74338
ClinVar
Submissions by phenotype
Hypercholesterolemia, familial, 1 Pathogenic:2Uncertain:1
Pathogenic, no assertion criteria provided | research | Laboratorium voor Moleculaire Diagnostiek Experimentele Vasculaire Geneeskunde, Academisch Medisch Centrum | - | - - |
Likely pathogenic, criteria provided, single submitter | literature only | LDLR-LOVD, British Heart Foundation | Mar 25, 2016 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | All of Us Research Program, National Institutes of Health | Dec 01, 2023 | This missense variant (also known as p.Leu411Val in the mature protein) replaces leucine with valine at codon 432 of the LDLR protein. Computational prediction suggests that this variant may have a deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). A functional study has shown that this variant does not disrupt LDLR function (PMID: 25647241). This variant has been reported in individuals affected with familial hypercholesterolemia (PMID: 10090484, 15199436, 29396260, 35047021). It has also been reported in individuals affected with early-onset myocardial infarction (PMID: 25487149, 25647241) and in individuals affected with coronary artery disease (PMID: 27050191). This variant has been identified in 4/251290 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. - |
Familial hypercholesterolemia Pathogenic:1Uncertain:2
Uncertain significance, criteria provided, single submitter | clinical testing | Color Diagnostics, LLC DBA Color Health | Apr 20, 2023 | This missense variant (also known as p.Leu411Val in the mature protein) replaces leucine with valine at codon 432 of the LDLR protein. Computational prediction suggests that this variant may have a deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). A functional study has shown that this variant does not disrupt LDLR function (PMID: 25647241). This variant has been reported in individuals affected with familial hypercholesterolemia (PMID: 10090484, 15199436, 29396260, 35047021). It has also been reported in individuals affected with early-onset myocardial infarction (PMID: 25487149, 25647241) and in individuals affected with coronary artery disease (PMID: 27050191). This variant has been identified in 4/251290 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. - |
Uncertain significance, no assertion criteria provided | clinical testing | Natera, Inc. | Feb 23, 2020 | - - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Invitae | Nov 28, 2023 | This sequence change replaces leucine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 432 of the LDLR protein (p.Leu432Val). This variant is present in population databases (rs730882100, gnomAD 0.006%). This missense change has been observed in individuals with clinical features of familial hypercholesterolemia (PMID: 10090484, 25487149, 25647241, 32770674, 35047021). This variant is also known as L411V. ClinVar contains an entry for this variant (Variation ID: 183111). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt LDLR protein function with a positive predictive value of 95%. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. - |
not provided Uncertain:1Other:1
not provided, no classification provided | in vitro | Dept. of Genetics and Pharmacogenomics, Merck Research Labs | - | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Sep 06, 2016 | Variant summary: The LDLR c.1294C>G (p.Leu432Val) variant involves the alteration of a non-conserved nucleotide. 3/4 in silico tools predict a damaging outcome for this variant (SNPs&GO not captured due to low reliability index). This variant was found in 3/120904 control chromosomes at a frequency of 0.0000248, which does not exceed the estimated maximal expected allele frequency of a pathogenic LDLR variant (0.0025031). This variant has been reported in affected individuals including FH, MI, and CAD, all without strong evidence for causality (i.e. co-segregation data). In addition, LDLR-LOVD, British Heart Foundation classified this variant as likely pathogenic, without evidence to independently evaluate. One published functional study showed that overexpression of p.Leu432Val resulted in intact cellular LDL uptake comparable to wild-type, although authors did list variant as a hypomorphic variant and speculated that the compound heterozygosity of two hypomorphic variants (Y465N and L432V for example) could impair receptor activities in the range of a classic FH-mutant (Thormaehlen_2015). JoJo Genetics noted that variant of interest often co-occured with Y465N (Y444N in legacy name) although the phase not well established. Taken together and due to conflicting lines of evidence, this variant is classified as VUS until more evidence becomes available. - |
LDLR-related disorder Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | PreventionGenetics, part of Exact Sciences | Nov 25, 2023 | The LDLR c.1294C>G variant is predicted to result in the amino acid substitution p.Leu432Val. This variant has also been reported in individuals with hypercholesterolemia and in controls in different reports (Thormaehlen et al. 2015. PubMed ID: 25647241; Do et al. 2015. PubMed ID: 25487149). It was also found in one individual who harbored the c.1393T>A (p.Tyr465Asn) variant that is also found in this patient, and it was suggested that together the two variants may form a hypomorphic allele, but further studies to confirm they are on the same allele were not performed (Thormaehlen et al. 2015. PubMed ID: 25647241). This variant is reported in 0.0065% of alleles in individuals of South Asian descent in gnomAD. This variant has been reported in ClinVar with interpretations of uncertain significance, likely pathogenic, and pathogenic (https://www.ncbi.nlm.nih.gov/clinvar/variation/183111/). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. - |
Cardiovascular phenotype Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | May 02, 2023 | The p.L432V variant (also known as c.1294C>G), located in coding exon 9 of the LDLR gene, results from a C to G substitution at nucleotide position 1294. The leucine at codon 432 is replaced by valine, an amino acid with highly similar properties. This variant (also referred to as L411V) has been detected in hypercholesterolemia cohorts, coronary artery disease cohorts, and myocardial infarction cohorts; however, in some cases, clinical detail was limited and/or the variant co-occurred with other variants in the LDLR gene, complicating interpretation of the impact of this variant alone (Ebhardt M et al. Hum. Mutat., 1999;13:257; Leren TP et al. Semin Vasc Med, 2004 Feb;4:75-85; Do R et al. Nature, 2015 Feb;518:102-6; Thormaehlen AS et al. PLoS Genet., 2015 Feb;11:e1004855; Khera AV et al. J. Am. Coll. Cardiol., 2016 06;67:2578-89; Hartgers ML et al. J Clin Lipidol Dec;12:390-396.e8; Rieck L et al. Clin Genet. 2020 Nov;98(5):457-467; Rimbert A et al. Front Genet. 2021 Jan;12:809256). This variant One in vitro assay reported this variant to be non-disruptive to LDL uptake; however, additional evidence is needed to confirm this finding (Thormaehlen AS et al. PLoS Genet., 2015 Feb;11:e1004855). This amino acid position is well conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. 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