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

Variant: NM_000527.5(LDLR):c.1720C>T (p.Arg574Cys)

CA023561

183123 (ClinVar)

Gene: LDLR
Condition: hypercholesterolemia, familial
Inheritance Mode: Semidominant inheritance
Link to MONDO
UUID: e9709543-f8c5-4cee-8658-2fcd762aa55a

HGVS expressions

NM_000527.5:c.1720C>T
NM_000527.5(LDLR):c.1720C>T (p.Arg574Cys)
NC_000019.10:g.11116873C>T
CM000681.2:g.11116873C>T
NC_000019.9:g.11227549C>T
CM000681.1:g.11227549C>T
NC_000019.8:g.11088549C>T
NG_009060.1:g.32493C>T
ENST00000558518.6:c.1720C>T
ENST00000252444.9:n.1974C>T
ENST00000455727.6:c.1216C>T
ENST00000535915.5:c.1597C>T
ENST00000545707.5:c.1339C>T
ENST00000557933.5:c.1720C>T
ENST00000558013.5:c.1720C>T
ENST00000558518.5:c.1720C>T
ENST00000559340.1:n.426+661C>T
NM_000527.4:c.1720C>T
NM_001195798.1:c.1720C>T
NM_001195799.1:c.1597C>T
NM_001195800.1:c.1216C>T
NM_001195803.1:c.1339C>T
NM_001195798.2:c.1720C>T
NM_001195799.2:c.1597C>T
NM_001195800.2:c.1216C>T
NM_001195803.2:c.1339C>T

Uncertain Significance

Met criteria codes 5
BS3_Supporting PS4_Supporting PP4 PP3 PM2
Not Met criteria codes 21
PVS1 BA1 BS2 BS4 BS1 BP5 BP7 BP2 BP3 BP4 BP1 PS2 PS3 PS1 PP1 PP2 PM6 PM3 PM1 PM4 PM5

Evidence Links 0

Expert Panel

Criteria Specification Information

Criteria Specification: ClinGen Familial Hypercholesterolemia Expert Panel Specifications to the ACMG/AMP Variant Classification Guidelines Version 1.1

PDF
Criteria Specification Approval History
Criteria Specifications for this VCEP
Evidence submitted by expert panel
Familial Hypercholesterolemia VCEP
NM_000527.5(LDLR):c.1720C>T (p.Arg574Cys) variant is classified as Uncertain significance - insufficient evidence for Familial Hypercholesterolemia by applying evidence codes (PM2, PP3, PP4, PS4_supporting and BS3_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 = 0.0001384 (0.01384%) in Other populations exomes+genomes (gnomAD v2.1.1). PP3 - REVEL = 0.967. PP4 - Variant meets PM2. Variant identified in 5 FH cases (1 case with Simon-Broome possible from 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 with Dutch Lipid Clinic Network score ≥ 6 published in PMID: 11462246; 1 case with Dutch Lipid Clinic Network score ≥ 6 published in PMID: 29290422; 1 case with Dutch Lipid Clinic Network score ≥ 6 from Research Lab of Molecular Genetics of Lipid Metabolism - Prof. M.Arca; 1 case with Simon-Broome register possible/definite published in PMID: 26892515. PS4_supporting - Variant meets PM2. Variant identified in 5 unrelated index cases (1 case with Simon-Broome from 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 with Dutch Lipid Clinic Network score ≥ 6 published in PMID: 11462246; 1 case with Dutch Lipid Clinic Network score ≥ 6 published in PMID: 29290422; 1 case with Dutch Lipid Clinic Network score ≥ 6 from Research Lab of Molecular Genetics of Lipid Metabolism - Prof. M.Arca; 1 case with Simon-Broome register criteria published in PMID: 26892515. BS3_supporting - PMID: 25647241: Level 3 assay - study on HeLa-Kyoto cells, LDLR-GFP construct, WB + CLSM assays, whole cycle is above 100% of wild-type activity. - functional study is consistent with no damaging effect.
Met criteria codes
BS3_Supporting
PMID: 25647241 - Level 3 assay - study on HeLa-Kyoto cells, LDLR-GFP construct, WB + CLSM assays, whole cycle is above 100% of wild-type activity. - functional study is consistent with no damaging effect
PS4_Supporting
Variant meets PM2. Variant identified in 5 unrelated index cases (1 case with Simon-Broome from 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 with Dutch Lipid Clinic Network score ≥ 6 published in PMID: 11462246; 1 case with Dutch Lipid Clinic Network score ≥ 6 published in PMID: 29290422; 1 case with Dutch Lipid Clinic Network score ≥ 6 from Research Lab of Molecular Genetics of Lipid Metabolism - Prof. M.Arca; 1 case with Simon-Broome register criteria published in PMID: 26892515.
PP4
Variant meets PM2. Variant identified in 5 FH cases (1 case with Simon-Broome possible from 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 with Dutch Lipid Clinic Network score ≥ 6 published in PMID: 11462246; 1 case with Dutch Lipid Clinic Network score ≥ 6 published in PMID: 29290422; 1 case with Dutch Lipid Clinic Network score ≥ 6 from Research Lab of Molecular Genetics of Lipid Metabolism - Prof. M.Arca; 1 case with Simon-Broome register possible/definite published in PMID: 26892515.
PP3
REVEL = 0.967
PM2
PopMax MAF = 0.0001384 (0.01384%) in Other populations exomes+genomes (gnomAD v2.1.1).
Not Met criteria codes
PVS1
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
BA1
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
BS2
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
BS4
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
BS1
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
BP5
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
BP7
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
BP2
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
BP3
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
BP4
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
BP1
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
PS2
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
PS3
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
PS1
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
PP1
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
PP2
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
PM6
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
PM3
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
PM1
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
PM4
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
PM5
2 other missense variants in the same codon: - NM_000527.5(LDLR):c.1721G>A (p.Arg574His) (ClinVar ID 251996) - Likely pathogenic by these guidelines - NM_000527.5(LDLR):c.1721G>T (p.Arg574Leu) (ClinVar ID 237867) - Uncertain significance by these guidelines There is no variant in the same codon classified as Pathogenic by these guidelines.
Approved on: 2022-03-07
Published on: 2022-07-12
The information on this website is not intended for direct diagnostic use or medical decision-making without review by a genetics professional. Individuals should not change their health behavior solely on the basis of information contained on this website. If you have questions about the information contained on this website, please see a health care professional.
¤ Powered by BCM's Genboree.