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Variant: NM_000527.5(LDLR):c.1784G>A (p.Arg595Gln)

CA023585

183126 (ClinVar)

Gene: LDLR
Condition: hypercholesterolemia, familial
Inheritance Mode: Semidominant inheritance
Link to MONDO
UUID: 812ea6ba-58f9-4dc4-b88d-13dc9626d34f
Approved on: 2022-02-02
Published on: 2022-07-11

HGVS expressions

NM_000527.5:c.1784G>A
NM_000527.5(LDLR):c.1784G>A (p.Arg595Gln)
NC_000019.10:g.11116937G>A
CM000681.2:g.11116937G>A
NC_000019.9:g.11227613G>A
CM000681.1:g.11227613G>A
NC_000019.8:g.11088613G>A
NG_009060.1:g.32557G>A
ENST00000558518.6:c.1784G>A
ENST00000252444.9:n.2038G>A
ENST00000455727.6:c.1280G>A
ENST00000535915.5:c.1661G>A
ENST00000545707.5:c.1403G>A
ENST00000557933.5:c.1784G>A
ENST00000558013.5:c.1784G>A
ENST00000558518.5:c.1784G>A
ENST00000559340.1:n.426+725G>A
NM_000527.4:c.1784G>A
NM_001195798.1:c.1784G>A
NM_001195799.1:c.1661G>A
NM_001195800.1:c.1280G>A
NM_001195803.1:c.1403G>A
NM_001195798.2:c.1784G>A
NM_001195799.2:c.1661G>A
NM_001195800.2:c.1280G>A
NM_001195803.2:c.1403G>A

Pathogenic

Met criteria codes 7
PM3 PM5 PM2 PS3_Supporting PS4 PP4 PP3
Not Met criteria codes 15
BA1 PM1 PM4 PM6 BS2 BS4 BS3 BS1 BP2 BP4 BP7 PVS1 PS2 PS1 PP1

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
The NM_000527.5(LDLR):c.1784G>A (p.Arg595Gln) variant is classified as Pathogenic for Familial Hypercholesterolemia by applying evidence codes (PM2, PP3, PM5, PS3_supporting, PS4, PP4, PM3) 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 = 0.0002389 (0.02389%) in European (Finnish) exomes+genomes (gnomAD v2.1.1), since this is a founder effect variant in Finnish population (PMID: 11585102) we can consider PopMax MAF = 0.00005012 (0.005012%) in East Asian exomes+genomes (gnomAD v2.1.1), so PM2 is Met. PP3 - REVEL = 0.956. It is above 0.75, so PP3 is Met. PM5 - 2 other missense variants in the same codon: - NM_000527.5(LDLR):c.1783C>T (p.Arg595Trp) (ClinVar ID: 161290) - Pathogenic by these guidelines - NM_000527.5(LDLR):c.1784G>T (p.Arg595Leu) (ClinVar ID: 252029) - Likely pathogenic by these guidelines There is 1 variant in the same codon classified as Pathogenic by these guidelines, so PM5 is Met. PS3_supporting - Level 3 assay: PMID 11585102: Heterozygous patient cells, 125I-LDL assays - result - 70% LDL-LDLR binding, 54-49% LDL-LDLR uptake and degradation. ---- functional study is consistent with damaging effect, so PS3_Supporting is Met. PS4 - Variant meets PM2 and is identified in 11 unrelated index cases: 1 index case with Simon Broome definite criteria from Molecular Genetics Laboratory (Centre for Cardiovascular Surgery and Transplantation), 4 index cases with DLCN criteria for FH (LDL > 95th percentile and presence of tendon xanthomas) from Finland (PMID: 11585102), 1 index case with FH criteria suggested by the Japan Atherosclerosis Society (TC > 260 mg/dL with tendon xanthomas OR TC > 260 mg/dL and TC > 260 mg/dL with tendon xanthomas in first or second degree relatives) from Japan ( PMID: 18718593), 1 index case with DLCN criteria for FH (score=8) from Sweden (PMID: 29974534), 1 index case with DLCN criteria for FH (score>=6) from Argentina (PMID: 30270055), 2 index cases with DLCN criteria for FH (score>=6) from Russia (PMID: 33418990), 1 index case with homozygous FH phenotype (LDL = 16 mmol/L) from The Netherlands (PMID: 24585268), so PS4 is Met. PP4 - Variant meets PM2 and is identified in 11 unrelated index cases as described before, so PP4 is Met. PM3 - Variant meets PM2 and is identified in an index case with homozygous FH phenotype (LDL = 16 mmol/L) and LDLR variant c.(1705+1_1706-1)_(*2514_?)del (described as 16kb deletion exon 12-18) (PMID: 24585268), classified as Pathogenic by these guidelines, in trans, so PM3 is Met.
Met criteria codes
PM3
Variant meets PM2 and is identified in an index case with homozygous FH phenotype (LDL = 16 mmol/L) and LDLR variant c.(1705+1_1706-1)_(*2514_?)del (described as 16kb deletion exon 12-18) (PMID: 24585268), classified as Pathogenic by these guidelines, in trans, so PM3 is Met.
PM5
2 other missense variants in the same codon: - NM_000527.5(LDLR):c.1783C>T (p.Arg595Trp) (ClinVar ID: 161290) - Pathogenic by these guidelines - NM_000527.5(LDLR):c.1784G>T (p.Arg595Leu) (ClinVar ID: 252029) - Likely pathogenic by these guidelines There is 1 variant in the same codon classified as Pathogenic by these guidelines, so PM5 is Met.
PM2
PopMax MAF = 0.0002389 (0.02389%) in European (Finnish) exomes+genomes (gnomAD v2.1.1), since this is a founder effect variant in Finnish population (PMID: 11585102) we can consider PopMax MAF = 0.00005012 (0.005012%) in East Asian exomes+genomes (gnomAD v2.1.1), so PM2 is Met.
PS3_Supporting
Level 3 assay: PMID 11585102: Heterozygous patient cells, 125I-LDL assays - result - 70% LDL-LDLR binding, 54-49% LDL-LDLR uptake and degradation. ---- functional study is consistent with damaging effect, so PS3_Supporting is Met.
PS4
Variant meets PM2 and is identified in 11 unrelated index cases: 1 index case with Simon Broome definite criteria from Molecular Genetics Laboratory (Centre for Cardiovascular Surgery and Transplantation), 4 index cases with DLCN criteria for FH (LDL > 95th percentile and presence of tendon xanthomas) from Finland (PMID: 11585102), 1 index case with FH criteria suggested by the Japan Atherosclerosis Society (TC > 260 mg/dL with tendon xanthomas OR TC > 260 mg/dL and TC > 260 mg/dL with tendon xanthomas in first or second degree relatives) from Japan ( PMID: 18718593), 1 index case with DLCN criteria for FH (score=8) from Sweden (PMID: 29974534), 1 index case with DLCN criteria for FH (score>=6) from Argentina (PMID: 30270055), 2 index cases with DLCN criteria for FH (score>=6) from Russia (PMID: 33418990), 1 index case with homozygous FH phenotype (LDL = 16 mmol/L) from The Netherlands (PMID: 24585268), so PS4 is Met.
PP4
Variant meets PM2 and is identified in 11 unrelated index cases: 1 index case with Simon Broome definite criteria from Molecular Genetics Laboratory (Centre for Cardiovascular Surgery and Transplantation), 4 index cases with DLCN criteria for FH (LDL > 95th percentile and presence of tendon xanthomas) from Finland (PMID: 11585102), 1 index case with FH criteria suggested by the Japan Atherosclerosis Society (TC > 260 mg/dL with tendon xanthomas OR TC > 260 mg/dL and TC > 260 mg/dL with tendon xanthomas in first or second degree relatives) from Japan ( PMID: 18718593), 1 index case with DLCN criteria for FH (score=8) from Sweden (PMID: 29974534), 1 index case with DLCN criteria for FH (score>=6) from Argentina (PMID: 30270055), 2 index cases with DLCN criteria for FH (score>=6) from Russia (PMID: 33418990), 1 index case with homozygous FH phenotype (LDL = 16 mmol/L) from The Netherlands (PMID: 24585268), so PP4 is Met.
PP3
REVEL = 0.956. It is above 0.75, so PP3 is Met.
Not Met criteria codes
BA1
FAF = 0.000002920 (0.0002920%) in European (non-Finnish) exomes+genomes (gnomAD v2.1.1), so BA1 is not met.
PM1
Variant meets PM2 but is not located in exon 4 or alters a cysteine residues, so PM1 is Not Met.
PM4
Variant meets PM2 and is missense, so PM4 is Not Met.
PM6
de novo occurrence data not reported, so PM6 is Not Met.
BS2
Not observed in 100 normolipidemic individuals from the Molecular Genetics Laboratory (Centre for Cardiovascular Surgery and Transplantation), so BS2 is Not Met.
BS4
Lack of segregation data not reported, so BS4 is Not Met.
BS3
Level 3 assays: PMID 25647241: HeLa-Kyoto cells and LDLR-GFP construct, laser-scanning confocal microscopy assays - result - assays only indicate expression of LDLR-GFP and uptake of DiI-LDL (not the whole LDLR cycle), so BS3_Supporting is not applicable.
BS1
FAF = 0.000002920 (0.0002920%) in European (non-Finnish) exomes+genomes (gnomAD v2.1.1), so BS1 is not met.
BP2
Variant meets PM2 and is identified in an index case with homozygous FH phenotype (LDL = 16 mmol/L) and LDLR variant c.(1705+1_1706-1)_(*2514_?)del (described as 16kb deletion exon 12-18) (PMID: 24585268), classified as Pathogenic by these guidelines, in trans, so BP2 is not met.
BP4
REVEL = 0.956. It is not below 0.50, so BP4 is Not Met.
BP7
Variant is not synonymous, so BP7 is Not Met.
PVS1
Variant is missense, so PVS1 is Not Met.
PS2
de novo occurrence data not reported, so PS2 is Not Met.
PS1
No more missense variants that lead to the same amino acid change, so PS1 is Not Met.
PP1
Segregation data not reported, so PP1 is Not Met.
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