ClinVar Miner

Submissions for variant NM_000527.5(LDLR):c.977C>G (p.Ser326Cys)

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Total submissions: 9
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
ClinGen Familial Hypercholesterolemia Variant Curation Expert Panel RCV000237360 SCV002506358 pathogenic Hypercholesterolemia, familial, 1 2022-04-05 reviewed by expert panel curation PP1_strong: Variant segregates with FH phenotype in at least 28 informative meiosis (minimum 2) from 9 families from different labs (Laboratory of Genetics and Molecular Cardiology). PS3: PMID: 32015373. Level 1 assay. Heterologous cells (CHO), FACS assays. Normal cell surface LDLR (90%), 50% binding and 48% uptake. PS4_supporting: variant meets PM2 and is identified in 1 index case who fulfills SB criteria of definite FH from Molecular Genetics Laboratory (Centre for Cardiovascular Surgery and Transplantation) and 1 index case with DLCN >6 from PMID 30270055, Corral et al., 2018 (Argentina) so PS4_Supporting is met PM2: No population data was found for this variant in gnomAD (gnomAD version 2.1.1). PP3: REVEL = 0.927. PP4: Variant meets PM2 and is identified in 1 index case who fulfils SB for FH from different labs (Molecular Genetics Laboratory (Centre for Cardiovascular Surgery and Transplantation) and Laboratory of Genetics and Molecular Cardiology).
LDLR-LOVD, British Heart Foundation RCV000237360 SCV000295122 likely pathogenic Hypercholesterolemia, familial, 1 2016-03-25 criteria provided, single submitter literature only
Molecular Genetics Laboratory, Centre for Cardiovascular Surgery and Transplantation RCV000237360 SCV000540779 likely pathogenic Hypercholesterolemia, familial, 1 2016-11-05 criteria provided, single submitter clinical testing
Laboratory of Genetics and Molecular Cardiology, University of São Paulo RCV000237360 SCV000588537 likely pathogenic Hypercholesterolemia, familial, 1 2016-03-01 criteria provided, single submitter research
Iberoamerican FH Network RCV000237360 SCV000748091 likely pathogenic Hypercholesterolemia, familial, 1 2016-03-01 criteria provided, single submitter research
Labcorp Genetics (formerly Invitae), Labcorp RCV001387171 SCV001587731 pathogenic Familial hypercholesterolemia 2024-08-01 criteria provided, single submitter clinical testing This sequence change replaces serine, which is neutral and polar, with cysteine, which is neutral and slightly polar, at codon 326 of the LDLR protein (p.Ser326Cys). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with familial hypercholesterolemia (PMID: 12820708, 23375686, 23815734, 25463123). This variant is also known as S305C. ClinVar contains an entry for this variant (Variation ID: 251581). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt LDLR protein function with a positive predictive value of 95%. This variant disrupts the p.Ser326 amino acid residue in LDLR. Other variant(s) that disrupt this residue have been observed in individuals with LDLR-related conditions (PMID: 11668640), which suggests that this may be a clinically significant amino acid residue. For these reasons, this variant has been classified as Pathogenic.
Fulgent Genetics, Fulgent Genetics RCV000237360 SCV002788296 likely pathogenic Hypercholesterolemia, familial, 1 2021-10-22 criteria provided, single submitter clinical testing
GENinCode PLC RCV001387171 SCV005622679 pathogenic Familial hypercholesterolemia 2025-01-09 criteria provided, single submitter clinical testing The LDLR c.977C>G p.(Ser326Cys) missense variant has been reported in at least 4 unrelated FH probands meeting clinical criteria, including patients where alternative causes of high cholesterol were excluded (PS4_SUPPORTING, PP4_SUPPORTING; PMIDs 23375686, 22698793, 30270055, ClinGen FH VCEP data) and has been seen to segregate with FH phenotype in >=6 informative meiosis (PP1_STRONG; ClinGen FH VCEP data, PMID: 23815734). This variant is absent from gnomAD v2.1.1 (PM2_MODERATE). This variant meets level 1 pathogenic functional study criteria with <70% of wild-type activity in LDL binding and LDL internalisation in heterologous cells (CHO) (PS3_STRONG; PMID: 32015373). REVEL score is 0.927 (PP3_SUPPORTING). Based on the evidence listed above, we have classified this variant as Pathogenic.
Laboratorium voor Moleculaire Diagnostiek Experimentele Vasculaire Geneeskunde, Academisch Medisch Centrum RCV000237360 SCV000606287 pathogenic Hypercholesterolemia, familial, 1 no assertion criteria provided research

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