rs137853965
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_000527.5(LDLR):c.2061dup(p.Asn688GlnfsTer29) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000372 in 1,613,984 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (★★). Synonymous variant affecting the same amino acid position (i.e. I687I) has been classified as Likely benign. Variant results in nonsense mediated mRNA decay.
Frequency
Consequence
NM_000527.5 frameshift
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 18 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
LDLR | NM_000527.5 | c.2061dup | p.Asn688GlnfsTer29 | frameshift_variant | 14/18 | ENST00000558518.6 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
LDLR | ENST00000558518.6 | c.2061dup | p.Asn688GlnfsTer29 | frameshift_variant | 14/18 | 1 | NM_000527.5 | P3 |
Frequencies
GnomAD3 genomes ? AF: 0.00000657 AC: 1AN: 152176Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.00000398 AC: 1AN: 251240Hom.: 0 AF XY: 0.00000736 AC XY: 1AN XY: 135836
GnomAD4 exome AF: 0.00000342 AC: 5AN: 1461808Hom.: 0 Cov.: 35 AF XY: 0.00000413 AC XY: 3AN XY: 727214
GnomAD4 genome ? AF: 0.00000657 AC: 1AN: 152176Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0AN XY: 74346
ClinVar
Submissions by phenotype
Hypercholesterolemia, familial, 1 Pathogenic:6
Pathogenic, no assertion criteria provided | clinical testing | Cardiovascular Genetics Laboratory, PathWest Laboratory Medicine WA - Fiona Stanley Hospital | Aug 25, 2008 | - - |
Pathogenic, criteria provided, single submitter | literature only | LDLR-LOVD, British Heart Foundation | Mar 25, 2016 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Revvity Omics, Revvity | Jul 06, 2022 | - - |
Pathogenic, criteria provided, single submitter | research | Brunham Lab, Centre for Heart and Lung Innovation, University of British Columbia | May 10, 2019 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | All of Us Research Program, National Institutes of Health | Nov 07, 2023 | The c.2061dup (p.Asn688Glnfs*29) variant in the LDLR gene introduces a premature translation termination codon resulting in an absent or disrupted protein product. The variant has been reported in multiple unrelated (>10) individuals who fulfill the clinical criteria of familial hypercholesterolemia (PMID: 16159606, 16389549, 17539906, 27680772, 22883975, 26046366, 24075752). Loss-of-function variants in LDLR are well known to be pathogenic (PMID: 33740630, 15321837, 20809525, 28645073). Truncating variants downstream of this variant are reported to be pathogenic in the literature (PMID: 22698793, 1301956, 9664576, 23375686) and by several ClinVar submitters (ClinVar ID: 252209, 252205, 252214, 1454247). This variant is found to be rare (1/251240; 0.00000398) in the general population database (gnomAD) and interpreted as pathogenic by multiple submitters in the ClinVar (ClinVar ID: 68103). Therefore, the c.2061dup (p.Asn688Glnfs*29) variant in the LDLR gene is classified as pathogenic. - |
Pathogenic, criteria provided, single submitter | research | Iberoamerican FH Network | Mar 01, 2016 | - - |
Familial hypercholesterolemia Pathogenic:4
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Jan 18, 2024 | This sequence change creates a premature translational stop signal (p.Asn688Glnfs*29) in the LDLR gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in LDLR are known to be pathogenic (PMID: 20809525, 28645073). This variant is present in population databases (rs751228587, gnomAD 0.002%). This premature translational stop signal has been observed in individuals with familial hypercholesterolemia (PMID: 16159606, 16389549, 17539906, 22883975, 26046366, 27680772). ClinVar contains an entry for this variant (Variation ID: 68103). For these reasons, this variant has been classified as Pathogenic. - |
Pathogenic, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Nov 27, 2017 | Variant summary: The LDLR c.2061dupC (p.Asn688GlnfsX29) variant results in a premature termination codon, predicted to cause a truncated or absent LDLR protein due to nonsense mediated decay, which are commonly known mechanisms for disease. One in silico tool predicts a damaging outcome for this variant. This variant was found in 2/246074 control chromosomes (in gnomAD) at a frequency of 0.0000081, which does not exceed the estimated maximal expected allele frequency of a pathogenic LDLR variant (0.0012508). The variant was reported in several individuals affected by definite FH (Graham 2005, Humphries 2006, Martin 2016) In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as pathogenic. Taken together, this variant is classified as pathogenic. - |
Pathogenic, criteria provided, single submitter | clinical testing | Human Genome Sequencing Center Clinical Lab, Baylor College of Medicine | Oct 15, 2018 | This c.2061dupC (p.Asn688Glnfs*29) variant in exon 14 of the LDLR gene results in an early stop codon. Loss of functions mutations in the LDLR gene are known to be a disease-causing mechanism. This variant has been reported in one patient with familial hypercholesterolaemia (PMID: 16389549). It has been reported at low allelic frequencies in the population database gnomAD (http://gnomad.broadinstitute.org/variant/19-11231118-T-TC). Therefore, the c.2061dupC (p.Asn688Glnfs*29) variant in the LDLR gene has been classified as a pathogenic variant. - |
Pathogenic, criteria provided, single submitter | clinical testing | Color Diagnostics, LLC DBA Color Health | Dec 08, 2020 | This variant inserts one nucleotide in exon 14 of the LDLR gene, creating a frameshift and premature translation stop signal. This variant is expected to result in an absent or non-functional protein product. To our knowledge, functional studies have not been reported for this variant. This variant has been reported in several individuals affected with familial hypercholesterolemia (PMID: 16159606, 16389549, 17539906, 22883975, 26046366, 27680772). This variant has been identified in 1/251240 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Loss of LDLR function is a known mechanism of disease (clinicalgenome.org). Based on the available evidence, this variant is classified as Pathogenic. - |
not provided Pathogenic:1Other:1
not provided, no classification provided | literature only | SNPedia | - | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Athena Diagnostics | Nov 04, 2016 | - - |
Homozygous familial hypercholesterolemia Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Apr 18, 2019 | The p.Asn688Glnfsx29 variant in LDLR has been identified in at least 10 individuals hypercholesterolemia (Graham 2005 Humphries 2006, Hooper 2012, Vandrovcova 2013, Johnston 2015, Abul-Husn 2016, Martin 2016) and has also been reported in ClinVar (Variation ID: 68103). It has been identified in 1/113654 European chromosomes by gnomAD (http://gnomad.broadinstitute.org). This variant is predicted to cause a frameshift, which alters the protein’s amino acid sequence beginning at position 688 and leads to a premature termination codon 29 amino acids downstream. This alteration is then predicted to lead to a truncated or absent protein. Heterozygous loss of function of the LDLR gene is an established disease mechanism in familial hypercholesterolemia. In summary, this variant meets criteria to be classified as pathogenic. ACMG/AMP Criteria applied: PVS1, PS4_Moderate, PM2. - |
Cardiovascular phenotype Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Ambry Genetics | May 12, 2022 | The c.2061dupC pathogenic mutation, located in coding exon 14 of the LDLR gene, results from a duplication of C at nucleotide position 2061, causing a translational frameshift with a predicted alternate stop codon (p.N688Qfs*29). This variant has been identified in multiple individuals with definite familial hypercholesterolemia (FH) or possible FH (Graham CA et al. Atherosclerosis, 2005 Oct;182:331-40; Humphries SE et al. J Mol Med (Berl), 2006 Mar;84:203-14; Taylor A et al. Clin Genet, 2007 Jun;71:561-8; Hooper AJ et al. Atherosclerosis, 2012 Oct;224:430-4; Faiz F et al. Atherosclerosis, 2013 Oct;230:249-55). In addition to the clinical data presented in the literature, this alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. As such, this alteration is interpreted as a disease-causing mutation. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at