19-11105579-AAATCTGACG-TGCA
Variant summary
Our verdict is Pathogenic. The variant received 19 ACMG points: 19P and 0B. PVS1PM2PP2PP5_Very_Strong
The NM_000527.5(LDLR):c.673_682delAAATCTGACGinsTGCA(p.Lys225_Glu228delinsCysLys) variant causes a stop gained, missense, disruptive inframe deletion change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic (★★). Variant results in nonsense mediated mRNA decay.
Frequency
Consequence
NM_000527.5 stop_gained, missense, disruptive_inframe_deletion
Scores
Clinical Significance
Conservation
Publications
- hypercholesterolemia, familial, 1Inheritance: AD, SD Classification: DEFINITIVE, STRONG Submitted by: Genomics England PanelApp, Labcorp Genetics (formerly Invitae), Laboratory for Molecular Medicine, ClinGen
- homozygous familial hypercholesterolemiaInheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
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ACMG classification
Our verdict: Pathogenic. The variant received 19 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
LDLR | NM_000527.5 | c.673_682delAAATCTGACGinsTGCA | p.Lys225_Glu228delinsCysLys | stop_gained, missense_variant, disruptive_inframe_deletion | Exon 4 of 18 | ENST00000558518.6 | NP_000518.1 |
Ensembl
Frequencies
GnomAD3 genomes Cov.: 33
GnomAD4 genome Cov.: 33
ClinVar
Submissions by phenotype
Familial hypercholesterolemia Pathogenic:2
Variant summary: LDLR c.673_682delinsTGCA (p.Lys225_Glu228delinsCysLys) results in an in-frame deletion-insertion that is predicted to delete 4 and insert 2 amino acids from the protein. The variant was absent in 151920 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.673_682delinsTGCA has been reported in the literature in individuals affected with Familial Hypercholesterolemia (Gabcova_2017). Additonally, variants affecting these amino acids are known to be pathogenic including the well known pathogenic variant c.682G>A (p.E228K). To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. ClinVar contains an entry for this variant (Variation ID: 2790080). Based on the evidence outlined above, the variant was classified as pathogenic. -
For these reasons, this variant has been classified as Pathogenic. This variant disrupts a region of the LDLR protein in which other variant(s) (p.Glu228Lys) have been determined to be pathogenic (PMID: 2318961, 18677035, 21475731, 21722902). This suggests that this is a clinically significant region of the protein, and that variants that disrupt it are likely to be disease-causing. This variant has not been reported in the literature in individuals affected with LDLR-related conditions. Information on the frequency of this variant in the gnomAD database is not available, as this variant may be reported differently in the database. This variant, c.673_682delinsTGCA, is a complex sequence change that results in the deletion of 4 and insertion of 2 amino acid(s) in the LDLR protein (p.Lys225_Glu228delinsCysLys). -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at