Total submissions: 6
Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
---|---|---|---|---|---|---|---|---|
Clin |
RCV000237544 | SCV002506401 | pathogenic | Hypercholesterolemia, familial, 1 | 2022-04-25 | reviewed by expert panel | curation | The NM_000527.5 (LDLR):c.1045C>T (p.Gln349Ter) variant is classified as Pathogenic for Familial Hypercholesterolemia by applying evidence codes (PM2, PVS1, PP4, PS4_Supporting, PM3, PP1_Moderate) as defined by the ClinGen Familial Hypercholesterolemia Expert Panel LDLR-specific variant curation guidelines (https://doi.org/10.1016/j.gim.2021.09.012). The supporting evidence is as follows: PM2: PopMax MAF = 0.00006 in South Asian population in gnomAD (gnomAD v2.1.1). PVS1: The variant causing a premature stop codon amino-terminal of amino acid 830 (NM_000527.5:p.Lys830). PP4: This variant meets PM2 and is identified in >1 index case who met clinical criteria for FH after alternative causes for high cholesterol were excluded. PS4_Supporting: Variant meets PM2, and is identified in 3 unrelated index cases: 1 case fulfil Simon Broome possible FH criteria (Centre de Génétique Moléculaire et Chromosomique, Unité de génétique de l'Obésité et des Dyslipidémies (APHP.Sorbonne Université, Hôpital de la Pitié-Salpêtrière); 1 case fulfil DLCN criteria (Robarts Research Institute, Canada); 1 case met criteria of total and LDL-C levels over the 95th percentile corrected for age and sex, plus two of: tendon xanthomata, premature coronary heart disease in the proband or in a first-degree relative and hypercholesterolemic children in the family (Instituto de Investigaciones Citológicas, Fundación Valenciana de Investigaciones Biomédicas, Valencia, Spain, PMID 11668640). PM3: Variant meets PM2 and is identified in an index case with homozygous FH phenotype (LDL-C: 11.1mmol/l at age of 5 yr.) and is homozygous for the variant (Robarts Research Institute, Canada). PP1_Moderate: Variant segregates with FH phenotype in 4 informative meiosis from 2 families from 2 research labs. One affected relative tested positive for the variant from one family (Centre de Génétique Moléculaire et Chromosomique, Unité de génétique de l'Obésité et des Dyslipidémies APHP.Sorbonne Université, Hôpital de la Pitié-Salpêtrière). Three affected relative tested positive for the variant from another family (Robarts Research Institute, Canada). |
LDLR- |
RCV000237544 | SCV000295157 | pathogenic | Hypercholesterolemia, familial, 1 | 2016-03-25 | criteria provided, single submitter | literature only | |
Centre de Génétique Moléculaire et Chromosomique, |
RCV000237544 | SCV000503285 | pathogenic | Hypercholesterolemia, familial, 1 | 2016-12-16 | criteria provided, single submitter | clinical testing | subject mutated among 2600 FH index cases screened = 1 , family member = 1 with co-segregation |
Fundacion Hipercolesterolemia Familiar | RCV000237544 | SCV000607547 | uncertain significance | Hypercholesterolemia, familial, 1 | 2016-03-01 | criteria provided, single submitter | research | |
Robarts Research Institute, |
RCV000237544 | SCV000782905 | pathogenic | Hypercholesterolemia, familial, 1 | 2018-01-02 | criteria provided, single submitter | clinical testing | |
Broad Institute Rare Disease Group, |
RCV000237544 | SCV001422911 | pathogenic | Hypercholesterolemia, familial, 1 | 2020-01-22 | criteria provided, single submitter | curation | The p.Gln349Ter (sometimes called p.Gln328Ter) variant in LDLR has been reported in 3 individuals (including 1 Spanish individual) with Familial Hypercholesterolemia, segregated with disease in 2 affected relatives from 1 family in the literature and ClinVar (PMID: 11668640; Variation ID: 251611), and has been identified in 0.006064% (1/16490) of South Asian chromosomes by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.org; dbSNP rs748300548). Although this variant has been seen in the general population, its frequency is low enough to be consistent with a dominant frequency for a disease with clinical variability/reduced penetrance. Please note that for diseases with clinical variability, or reduced penetrance, pathogenic variants may be present at a low frequency in the general population. The number of reported affected individuals with this variant is slightly greater than expected compared to non-affected individuals with this variant. This variant has also been reported as a VUS and a pathogenic variant in ClinVar (Variation ID: 251611). This nonsense variant leads to a premature termination codon at position 349, which is predicted to lead to a truncated or absent protein. Heterozygous loss of function of the LDLR gene is an established disease mechanism in Familial Hypercholesterolemia. In summary, this variant meets criteria to be classified as pathogenic for Familial Hypercholesterolemia in an autosomal dominant manner based on the predicted impact of the variant and multiple occurrences in individuals with Familial Hypercholesterolemia. ACMG/AMP Criteria applied: PVS1, PM2_Supporting, PS4_Supporting (Richards 2015). |