Evidence Repository - Clinical Genome Resources

The ClinGen Evidence Repository is an FDA-recognized human genetic variant database containing expert-curated assertions regarding variants' pathogenicity and supporting evidence summaries. [Disclaimer]

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Variant: NM_000527.5(LDLR):c.1003G>A (p.Gly335Ser)

CA023402

183105 (ClinVar)

Gene: LDLR

Condition: hypercholesterolemia, familial

Inheritance Mode: Semidominant inheritance

Link to MONDO

UUID: 50e4f7aa-2e0a-433c-88ba-08d28e21d8e2

Approved on: 2023-04-28

Published on: 2023-05-01

HGVS expressions

NM_000527.5:c.1003G>A

NM_000527.5(LDLR):c.1003G>A (p.Gly335Ser)

NC_000019.10:g.11110714G>A

CM000681.2:g.11110714G>A

NC_000019.9:g.11221390G>A

CM000681.1:g.11221390G>A

NC_000019.8:g.11082390G>A

NG_009060.1:g.26334G>A

ENST00000558518.6:c.1003G>A

ENST00000252444.9:n.1257G>A

ENST00000455727.6:c.499G>A

ENST00000535915.5:c.880G>A

ENST00000545707.5:c.622G>A

ENST00000557933.5:c.1003G>A

ENST00000558013.5:c.1003G>A

ENST00000558518.5:c.1003G>A

ENST00000560173.1:n.2G>A

ENST00000560467.1:n.541-800G>A

NM_000527.4:c.1003G>A

NM_001195798.1:c.1003G>A

NM_001195799.1:c.880G>A

NM_001195800.1:c.499G>A

NM_001195803.1:c.622G>A

NM_001195798.2:c.1003G>A

NM_001195799.2:c.880G>A

NM_001195800.2:c.499G>A

NM_001195803.2:c.622G>A

Likely Pathogenic

The Expert Panel has overridden the computationally generated classification - "Uncertain Significance - Insufficient Evidence"

PS4_Supporting PP4 PP3 PM2 PS3_Supporting

PP1 PP2 BA1 PM6 PM3 PM1 PM4 PM5 BS2 BS4 BS3 BS1 PVS1 PS2 PS1 BP5 BP7 BP2 BP3 BP4 BP1

Evidence Links 0

Expert Panel

Familial Hypercholesterolemia VCEP

Criteria Specification Information

Criteria Specification: ClinGen Familial Hypercholesterolemia Expert Panel Specifications to the ACMG/AMP Variant Classification Guidelines Version 1.2

Criteria Specification Approval History

Criteria Specifications for this VCEP

Evidence submitted by expert panel

Familial Hypercholesterolemia VCEP

The NM_000527.5(LDLR):c.1003G>A (p.Gly335Ser) variant is classified as Likely pathogenic for Familial Hypercholesterolemia by applying evidence codes PM2, PP3, PP4, PS3_Supporting and PS4_Supporting 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 = 0.00005431 (0.005431%) in European non-Finnish exomes (gnomAD v2.1.1). It is below 0.02%, so PM2 is met. PP3 - REVEL = 0.843. It is above 0.75, so PP3 is met. PS4_supporting - variant meets PM2 and was identified in: - 3 unrelated index cases who fulfill Dutch lipid clinic network >=6 from Robarts Research Institute, Canada; - at least 1 index case with Dutch Lipid Clinic Scoring : Definite FH from U4M - Lille University & CHRU Lille, Université de Lille - CHRU de Lille (SCV000583773.1), France; - 1 index case with DLNC > or = 6 from Bañares et al. 2017 (PMID: 28502510), Argentina; at least 5 unrelated index cases with clinical FH criteria, so PP4 is met. PP4 - variant meets PM2 and was identified in at least 5 unrelated index cases with clinical FH criteria (see PS4_Supporting for details), so PP4 is met. PS3_supporting - Level 3 FS: Hobbs et al. 1992 (PMID: 1301956): Heterozygous patients' fibroblasts, 125I-LDL assays - results: 30-40% LDLR activity. --- activity is below 85% of wild-type, so PS3_Supporting is met.

PS4_Supporting

variant meets PM2 and was identified in: - 3 unrelated index cases who fulfill Dutch lipid clinic network >=6 from Robarts Research Institute, Canada; - at least 1 index case with Dutch Lipid Clinic Scoring : Definite FH from U4M - Lille University & CHRU Lille, Université de Lille - CHRU de Lille (SCV000583773.1), France; - 1 index case with DLNC > or = 6 from Bañares et al. 2017 (PMID: 28502510), Argentina at least 5 unrelated index cases, so PS4_Supporting is met

PP4

PP3

REVEL = 0.843. It is above 0.75, so PP3 is met

PM2

PopMax MAF = 0.00005431 (0.005431%) in European non-Finnish exomes (gnomAD v2.1.1). It is below 0.02%, so PM2 is met

PS3_Supporting

Level 3 FS: Thormaehlen et al. 2015 (PMID: 25647241): In vitro studies where the variant is introduced into LDLR'-GFP and transiently expressed in He-La cells- results: variant slightly decreases LDL expression, but it is not significantly altered compared to WT. --- Hobbs et al., 1992 study represents more accurately biological function, so this study is disregarded. Level 3 FS: Hobbs et al. 1992 (PMID: 1301956): Heterozygous patients' fibroblasts, 125I-LDL assays - results: 30-40% LDLR activity. --- activity is below 85% of wild-type, so PS3_Supporting is met

PP1

no segregation data

PP2

not applicable

BA1

FAF = 0.00002298 (0.002298%) in European non-Finnish exomes (gnomAD v2.1.1). It is not above 0.5%, so not met

PM6

no de novo occurrence

PM3

variant identified in 1 index case with LDL = 243mg/dl under medication (40mg rosuvastatin and 10mg ezetimibe) (calculated untreated LDL = 243/0.7 = 347mg/dl) who is a compound heterozygote in trans with LDLR: c.1731G>C, p.Trp577Cys, from Laboratory of Genetics and Molecular Cardiology, Brasil. --- index case does not have a clearly homozygous phenotype (untreated LDL>500mg/dl), so PM3 is not met

PM1

variant is missense and meets PM2, but it is not in exon 4 and does not alter Cys, so not met

PM4

variant is missense, so not met

PM5

There are 4 other missense variants in the same codon: NM_000527.4(LDLR):c.1003G>C, p.(Gly335Arg) (ClinVar ID 926520) - classified as VUS by these guidelines NM_000527.4(LDLR):c.1004G>A, p.(Gly335Asp) (ClinVar ID 225181) - classified as VUS by these guidelines NM_000527.4(LDLR):c.1004G>T, p.(Gly335Val) (ClinVar ID 251587) - classified as VUS by these guidelines NM_000527.5(LDLR):c.1003G>T (p.Gly335Cys) (ClinVar ID 1395739) - classified as Likely pathogenic by these guidelines. There is no Pathogenic variant in the same codon, so not met

BS2

variant was not identified in normolipidemic individuals: 0/1000 controls from Robarts Research Institute, so not met

BS4

no segregation data

BS3

Level 3 FS: Thormaehlen et al. 2015 (PMID: 25647241): In vitro studies where the variant is introduced into LDLR'-GFP and transiently expressed in He-La cells- results: variant slightly decreases LDL expression, but it is not significantly altered compared to WT. --- this study does not test the whole LDLR cycle, so not met Level 3 FS: Hobbs et al. 1992 (PMID: 1301956): Heterozygous patients' fibroblasts, 125I-LDL assays - results: 30-40% LDLR activity. --- activity is not above 95% of wild-type, so BS3_Supporting is not met

BS1

FAF = 0.00002298 (0.002298%) in European non-Finnish exomes (gnomAD v2.1.1). It is not above 0.2%, so not met

PVS1

variant is missense and not in initiation codon, so not met

PS2

no de novo occurrence

PS1

There is no other variant that leads to the same amino acid change, so not met

BP5

not applicable

BP7

variant is missense, so not met

BP2

variant identified in 1 index case with LDL = 243mg/dl under medication (40mg rosuvastatin and 10mg ezetimibe) (calculated untreated LDL = 243/0.7 = 347mg/dl) who is a compound heterozygote in trans with LDLR: c.1731G>C, p.Trp577Cys, from Laboratory of Genetics and Molecular Cardiology, Brasil. --- index case does not have a clearly heterozygous phenotype (untreated LDL>310mg/dl), so BP2 is not met

BP3

not applicable

BP4

REVEL = 0.843. It is not below 0.50, so BP4 is not met

BP1

not applicable

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