Our verdict is Pathogenic. The variant received 13 ACMG points: 13P and 0B. PM1PM2PM5PP2PP3_StrongPP5_Moderate
The NM_000527.5(LDLR):c.1426C>T(p.Pro476Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P476R) has been classified as Uncertain significance.
LDLR (HGNC:6547): (low density lipoprotein receptor) The low density lipoprotein receptor (LDLR) gene family consists of cell surface proteins involved in receptor-mediated endocytosis of specific ligands. The encoded protein is normally bound at the cell membrane, where it binds low density lipoprotein/cholesterol and is taken into the cell. Lysosomes release the cholesterol, which is made available for repression of microsomal enzyme 3-hydroxy-3-methylglutaryl coenzyme A (HMG CoA) reductase, the rate-limiting step in cholesterol synthesis. At the same time, a reciprocal stimulation of cholesterol ester synthesis takes place. Mutations in this gene cause the autosomal dominant disorder, familial hypercholesterolemia. Alternate splicing results in multiple transcript variants.[provided by RefSeq, May 2022]
MIR6886 (HGNC:50121): (microRNA 6886) microRNAs (miRNAs) are short (20-24 nt) non-coding RNAs that are involved in post-transcriptional regulation of gene expression in multicellular organisms by affecting both the stability and translation of mRNAs. miRNAs are transcribed by RNA polymerase II as part of capped and polyadenylated primary transcripts (pri-miRNAs) that can be either protein-coding or non-coding. The primary transcript is cleaved by the Drosha ribonuclease III enzyme to produce an approximately 70-nt stem-loop precursor miRNA (pre-miRNA), which is further cleaved by the cytoplasmic Dicer ribonuclease to generate the mature miRNA and antisense miRNA star (miRNA*) products. The mature miRNA is incorporated into a RNA-induced silencing complex (RISC), which recognizes target mRNAs through imperfect base pairing with the miRNA and most commonly results in translational inhibition or destabilization of the target mRNA. The RefSeq represents the predicted microRNA stem-loop. [provided by RefSeq, Sep 2009]
Our verdict: Pathogenic. The variant received 13 ACMG points.
PM1
In a hotspot region, there are 18 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 3 benign, 21 uncertain in NM_000527.5
PM2
Very rare variant in population databases, with high coverage;
PM5
Other missense variant is known to change same aminoacid residue: Variant chr19-11113603-C-T is described in CliVar as Pathogenic. Clinvar id is 430777.Status of the report is criteria_provided_single_submitter, 1 stars.
PP2
Missense variant in the gene, where a lot of missense mutations are associated with disease in ClinVar. The gene has 678 curated pathogenic missense variants (we use a threshold of 10). The gene has 92 curated benign missense variants. Gene score misZ: 0.12407 (below the threshold of 3.09). Trascript score misZ: 0.59338 (below the threshold of 3.09). GenCC associations: The gene is linked to hypercholesterolemia, familial, 1, homozygous familial hypercholesterolemia.
PP3
MetaRNN computational evidence supports a deleterious effect, 0.993
PP5
Variant 19-11113602-C-T is Pathogenic according to our data. Variant chr19-11113602-C-T is described in CliVar as Likely_pathogenic. Clinvar id is 251837.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr19-11113602-C-T is described in CliVar as Likely_pathogenic. Clinvar id is 251837.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr19-11113602-C-T is described in CliVar as Likely_pathogenic. Clinvar id is 251837.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr19-11113602-C-T is described in CliVar as Likely_pathogenic. Clinvar id is 251837.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr19-11113602-C-T is described in CliVar as Likely_pathogenic. Clinvar id is 251837.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr19-11113602-C-T is described in CliVar as Likely_pathogenic. Clinvar id is 251837.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr19-11113602-C-T is described in CliVar as Likely_pathogenic. Clinvar id is 251837.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr19-11113602-C-T is described in CliVar as Likely_pathogenic. Clinvar id is 251837.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr19-11113602-C-T is described in CliVar as Likely_pathogenic. Clinvar id is 251837.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr19-11113602-C-T is described in CliVar as Likely_pathogenic. Clinvar id is 251837.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr19-11113602-C-T is described in CliVar as Likely_pathogenic. Clinvar id is 251837.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr19-11113602-C-T is described in CliVar as Likely_pathogenic. Clinvar id is 251837.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr19-11113602-C-T is described in CliVar as Likely_pathogenic. Clinvar id is 251837.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr19-11113602-C-T is described in CliVar as Likely_pathogenic. Clinvar id is 251837.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr19-11113602-C-T is described in CliVar as Likely_pathogenic. Clinvar id is 251837.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr19-11113602-C-T is described in CliVar as Likely_pathogenic. Clinvar id is 251837.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr19-11113602-C-T is described in CliVar as Likely_pathogenic. Clinvar id is 251837.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr19-11113602-C-T is described in CliVar as Likely_pathogenic. Clinvar id is 251837.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr19-11113602-C-T is described in CliVar as Likely_pathogenic. Clinvar id is 251837.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr19-11113602-C-T is described in CliVar as Likely_pathogenic. Clinvar id is 251837.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr19-11113602-C-T is described in CliVar as Likely_pathogenic. Clinvar id is 251837.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr19-11113602-C-T is described in CliVar as Likely_pathogenic. Clinvar id is 251837.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr19-11113602-C-T is described in CliVar as Likely_pathogenic. Clinvar id is 251837.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr19-11113602-C-T is described in CliVar as Likely_pathogenic. Clinvar id is 251837.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr19-11113602-C-T is described in CliVar as Likely_pathogenic. Clinvar id is 251837.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr19-11113602-C-T is described in CliVar as Likely_pathogenic. Clinvar id is 251837.Status of the report is criteria_provided_single_submitter, 1 stars.