rs875989920
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_000527.5(LDLR):c.1371_1374dup(p.Ala459GlnfsTer9) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,638 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. L456L) 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.1371_1374dup | p.Ala459GlnfsTer9 | frameshift_variant | 10/18 | ENST00000558518.6 | |
MIR6886 | NR_106946.1 | downstream_gene_variant |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
LDLR | ENST00000558518.6 | c.1371_1374dup | p.Ala459GlnfsTer9 | frameshift_variant | 10/18 | 1 | NM_000527.5 | P3 | |
MIR6886 | ENST00000619864.1 | downstream_gene_variant |
Frequencies
GnomAD3 genomes Cov.: 31
GnomAD4 exome AF: 6.84e-7 AC: 1AN: 1461638Hom.: 0 Cov.: 38 AF XY: 0.00000138 AC XY: 1AN XY: 727124
GnomAD4 genome Cov.: 31
ClinVar
Submissions by phenotype
Hypercholesterolemia, familial, 1 Pathogenic:3
Pathogenic, no assertion criteria provided | clinical testing | Cardiovascular Genetics Laboratory, PathWest Laboratory Medicine WA - Fiona Stanley Hospital | Mar 11, 2013 | - - |
Pathogenic, criteria provided, single submitter | literature only | LDLR-LOVD, British Heart Foundation | Mar 25, 2016 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | All of Us Research Program, National Institutes of Health | Jan 06, 2024 | The c.1371_1374dup (p.Ala459Glnfs*9) variant in the LDLR gene, that encodes for low density lipoprotein receptor, introduces a premature translation termination codon resulting in an absent or disrupted protein product. The variant has been reported in at least six individuals affected with familial hypercholesterolemia (FH) (PMID: 7866407, 9259195, 34037665). Loss-of-function variants in LDLR are known to be pathogenic (PMID: 33740630, 15321837, 20809525, 28645073). Truncating variants downstream of this variant are reported to be pathogenic in the literature (PMID:23375686, 25846081, 27170061) and by several ClinVar submitters (ClinVar ID:1071946, 226356). This variant is found to be absent in the general population database (gnomAD) and interpreted as pathogenic by multiple submitters in ClinVar (ClinVar ID: 226355). Therefore, the c.1371_1374dup (p.Ala459Glnfs*9) variant in the LDLR gene is classified as pathogenic. - |
Familial hypercholesterolemia Pathogenic:2
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Jul 22, 2023 | For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 226355). This premature translational stop signal has been observed in individual(s) with hypercholesterolemia (PMID: 7866407). This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Ala459Glnfs*9) 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). - |
Pathogenic, criteria provided, single submitter | clinical testing | Human Genome Sequencing Center Clinical Lab, Baylor College of Medicine | Sep 21, 2023 | The c.1371_1374dup (p.Ala459Glnfs*9) variant in the LDLR gene, that encodes for low density lipoprotein receptor, introduces a premature translation termination codon resulting in an absent or disrupted protein product. The variant has been reported in at least six individuals affected with familial hypercholesterolemia (FH) (PMID: 7866407, 9259195, 34037665). Loss-of-function variants in LDLR are known to be pathogenic (PMID: 33740630, 15321837, 20809525, 28645073). Truncating variants downstream of this variant are reported to be pathogenic in the literature (PMID:23375686, 25846081, 27170061) and by several ClinVar submitters (ClinVar ID:1071946, 226356). This variant is found to be absent in the general population database (gnomAD) and interpreted as pathogenic by multiple submitters in ClinVar (ClinVar ID: 226355). Therefore, the c.1371_1374dup (p.Ala459Glnfs*9) variant in the LDLR gene is classified as pathogenic. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at