Total submissions: 4
Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
---|---|---|---|---|---|---|---|---|
Clin |
RCV000238008 | SCV002817126 | likely pathogenic | Hypercholesterolemia, familial, 1 | 2022-08-29 | reviewed by expert panel | curation | The NM_000527.4(LDLR):c.-149C>A variant is classified as Likely pathogenic for Familial Hypercholesterolemia by applying evidence codes (PM2, PS4, PP4, PP1_moderate) as defined by the ClinGen Familial Hypercholesterolemia Expert Panel LDLR-specific variant curation guidelines (https://doi.org/10.1101/2021.03.17.21252755). The supporting evidence is as follows: PM2 - This variant is absent from gnomAD (gnomAD v2.1.1), so PM2 is Met. PS4 - Variant meets PM2 and is identified in 10 unrelated index cases who fulfill Simon Broome criteria for FH (4 definite FH and 6 possible FH) from Molecular Genetics Laboratory (Centre for Cardiovascular Surgery and Transplantation)(PMID: 28379029), so PS4 is Met. PP4 - Variant meets PM2 and is identified in 10 unrelated index cases who fulfill Simon Broome criteria for FH (see PS4 for details), so PP4 is Met. PP1_Moderate - Variant segregates with FH phenotype in 4 informative meiosis from 3 families from Molecular Genetics Laboratory (Centre for Cardiovascular Surgery and Transplantation)(PMID: 28379029), so PP1_Moderate is Met. |
LDLR- |
RCV000238008 | SCV000294381 | uncertain significance | Hypercholesterolemia, familial, 1 | 2016-03-25 | criteria provided, single submitter | literature only | |
Molecular Genetics Laboratory, |
RCV000238008 | SCV000540709 | likely pathogenic | Hypercholesterolemia, familial, 1 | 2016-11-05 | criteria provided, single submitter | clinical testing | Disrupt Sterol Regulatory Element sequence. |
Invitae | RCV003581589 | SCV004298004 | likely pathogenic | Familial hypercholesterolemia | 2024-01-15 | criteria provided, single submitter | clinical testing | This variant occurs in a non-coding region of the LDLR gene. It does not change the encoded amino acid sequence of the LDLR protein. This variant is not present in population databases (gnomAD no frequency). This variant has been observed in individuals with familial hypercholesterolemia (PMID: 22698793, 28379029). ClinVar contains an entry for this variant (Variation ID: 250946). In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. |