Our verdict is Pathogenic. The variant received 10 ACMG points: 10P and 0B. PVS1PP5_Moderate
The NM_000527.5(LDLR):c.2050_2063delGCCCCGCAGATCAA(p.Ala684ProfsTer28) variant causes a frameshift change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. It is difficult to determine the true allele frequency of this variant because it is of type DEL_BIG, and the frequency of such variant types in population databases may be underestimated and unreliable. Variant has been reported in ClinVar as Pathogenic (★). Synonymous variant affecting the same amino acid position (i.e. A684A) has been classified as Likely benign. Variant results in nonsense mediated mRNA decay.
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]
LDLR Gene-Disease associations (from GenCC):
hypercholesterolemia, familial, 1
Inheritance: AD, SD Classification: DEFINITIVE, STRONG Submitted by: Genomics England PanelApp, Labcorp Genetics (formerly Invitae), Laboratory for Molecular Medicine, ClinGen
homozygous familial hypercholesterolemia
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
Our verdict: Pathogenic. The variant received 10 ACMG points.
PVS1
Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
PP5
Variant 19-11120431-TGCCCCGCAGATCAA-T is Pathogenic according to our data. Variant chr19-11120431-TGCCCCGCAGATCAA-T is described in CliVar as Pathogenic. Clinvar id is 252191.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr19-11120431-TGCCCCGCAGATCAA-T is described in CliVar as Pathogenic. Clinvar id is 252191.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr19-11120431-TGCCCCGCAGATCAA-T is described in CliVar as Pathogenic. Clinvar id is 252191.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr19-11120431-TGCCCCGCAGATCAA-T is described in CliVar as Pathogenic. Clinvar id is 252191.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr19-11120431-TGCCCCGCAGATCAA-T is described in CliVar as Pathogenic. Clinvar id is 252191.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr19-11120431-TGCCCCGCAGATCAA-T is described in CliVar as Pathogenic. Clinvar id is 252191.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr19-11120431-TGCCCCGCAGATCAA-T is described in CliVar as Pathogenic. Clinvar id is 252191.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr19-11120431-TGCCCCGCAGATCAA-T is described in CliVar as Pathogenic. Clinvar id is 252191.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr19-11120431-TGCCCCGCAGATCAA-T is described in CliVar as Pathogenic. Clinvar id is 252191.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr19-11120431-TGCCCCGCAGATCAA-T is described in CliVar as Pathogenic. Clinvar id is 252191.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr19-11120431-TGCCCCGCAGATCAA-T is described in CliVar as Pathogenic. Clinvar id is 252191.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr19-11120431-TGCCCCGCAGATCAA-T is described in CliVar as Pathogenic. Clinvar id is 252191.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr19-11120431-TGCCCCGCAGATCAA-T is described in CliVar as Pathogenic. Clinvar id is 252191.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr19-11120431-TGCCCCGCAGATCAA-T is described in CliVar as Pathogenic. Clinvar id is 252191.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr19-11120431-TGCCCCGCAGATCAA-T is described in CliVar as Pathogenic. Clinvar id is 252191.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr19-11120431-TGCCCCGCAGATCAA-T is described in CliVar as Pathogenic. Clinvar id is 252191.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr19-11120431-TGCCCCGCAGATCAA-T is described in CliVar as Pathogenic. Clinvar id is 252191.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr19-11120431-TGCCCCGCAGATCAA-T is described in CliVar as Pathogenic. Clinvar id is 252191.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr19-11120431-TGCCCCGCAGATCAA-T is described in CliVar as Pathogenic. Clinvar id is 252191.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr19-11120431-TGCCCCGCAGATCAA-T is described in CliVar as Pathogenic. Clinvar id is 252191.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr19-11120431-TGCCCCGCAGATCAA-T is described in CliVar as Pathogenic. Clinvar id is 252191.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr19-11120431-TGCCCCGCAGATCAA-T is described in CliVar as Pathogenic. Clinvar id is 252191.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr19-11120431-TGCCCCGCAGATCAA-T is described in CliVar as Pathogenic. Clinvar id is 252191.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr19-11120431-TGCCCCGCAGATCAA-T is described in CliVar as Pathogenic. Clinvar id is 252191.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr19-11120431-TGCCCCGCAGATCAA-T is described in CliVar as Pathogenic. Clinvar id is 252191.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr19-11120431-TGCCCCGCAGATCAA-T is described in CliVar as Pathogenic. Clinvar id is 252191.Status of the report is criteria_provided_single_submitter, 1 stars.