Total submissions: 5
Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
---|---|---|---|---|---|---|---|---|
Clin |
RCV000237722 | SCV004022446 | likely pathogenic | Hypercholesterolemia, familial, 1 | 2023-04-28 | reviewed by expert panel | curation | The NM_000527.5(LDLR):c.1942T>C (p.Ser648Pro) variant is classified as Likely pathogenic for Familial Hypercholesterolemia by applying evidence codes (PS3, PM2 and PP4) 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: PS3 - 2 Level 1 assays: PMID 25386756: Heterologous cells (CHO), FACS assays - result - 50% cell surface LDLR and binding and 26% uptake. PMID 23021490: Heterologous cells (CHO), 125I-LDL and WB assays - result - 30-50% LDLR activity; reduced mature protein. ---- activity is below 70% of wild-type, so functional studies are consistent with damaging effect and PS3 is Met. PM2 - This variant is absent from gnomAD (gnomAD v2.1.1), so PM2 is Met. PP4 - Variant meets PM2 and is identified in 1 index cases who fulfills SB possible criteria for FH from Cardiovascular Research Group, Instituto Nacional de Saude Doutor Ricardo Jorge, so PP4 is met. |
LDLR- |
RCV000237722 | SCV000295762 | likely pathogenic | Hypercholesterolemia, familial, 1 | 2016-03-25 | criteria provided, single submitter | literature only | |
Cardiovascular Research Group, |
RCV000237722 | SCV000322990 | likely pathogenic | Hypercholesterolemia, familial, 1 | 2016-03-01 | criteria provided, single submitter | research | 0/200 non-FH alleles |
Gene |
RCV002461042 | SCV002757358 | likely pathogenic | not provided | 2022-05-23 | criteria provided, single submitter | clinical testing | Published functional studies demonstrate a damaging effect as expression in transfected cell lines is significantly reduced (Etxebarria A et al., 2014); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Reported as S627P using alternate nomenclature in an individual with familial hypercholesterolemia (Bourbon M et al., 2008); This variant is associated with the following publications: (PMID: 23021490, 25386756, 17765246) |
Women's Health and Genetics/Laboratory Corporation of America, |
RCV003235162 | SCV003934620 | likely pathogenic | Familial hypercholesterolemia | 2023-05-22 | criteria provided, single submitter | clinical testing | Variant summary: LDLR c.1942T>C (p.Ser648Pro) results in a non-conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant was absent in 251468 control chromosomes (gnomAD). c.1942T>C has been reported in the literature in at least one individual affected with Hypercholesterolemia (Bourbon_2008). At least two publications reports experimental evidence evaluating an impact on protein function, finding substantially decreased mature LDLR protein and impaired uptake and degredation of LDL (Silva_2012, Etxebarria_2014). The following publications have been ascertained in the context of this evaluation (PMID: 17765246, 23021490, 25386756). Three submitters have provided clinical-significance assessments for this variant to ClinVar after 2014, and classified the variant as likely pathogenic. Based on the evidence outlined above, the variant was classified as likely pathogenic. |