Variant: NM_000527.5(LDLR):c.1285G>C (p.Val429Leu)

CA10576303

226353 (ClinVar)

Gene: LDLR

Condition: hypercholesterolemia, familial

Inheritance Mode: Semidominant inheritance

UUID: b5d5eda5-5692-4db4-b70c-072b97df27b6

Approved on: 2023-03-27

Published on: 2024-10-04

HGVS expressions

NM_000527.5:c.1285G>C
NM_000527.5(LDLR):c.1285G>C (p.Val429Leu)
NC_000019.10:g.11113376G>C
CM000681.2:g.11113376G>C
NC_000019.9:g.11224052G>C
CM000681.1:g.11224052G>C
NC_000019.8:g.11085052G>C
NG_009060.1:g.28996G>C
ENST00000252444.10:c.1543G>C
ENST00000559340.2:c.1285G>C
ENST00000560467.2:c.1165G>C
ENST00000558518.6:c.1285G>C
ENST00000252444.9:c.1539G>C
ENST00000455727.6:c.781G>C
ENST00000535915.5:c.1162G>C
ENST00000545707.5:c.904G>C
ENST00000557933.5:c.1285G>C
ENST00000558013.5:c.1285G>C
ENST00000558518.5:c.1285G>C
ENST00000559340.1:c.6G>C
ENST00000560173.1:n.284G>C
ENST00000560467.1:c.765G>C
NM_000527.4:c.1285G>C
NM_001195798.1:c.1285G>C
NM_001195799.1:c.1162G>C
NM_001195800.1:c.781G>C
NM_001195803.1:c.904G>C
NM_001195798.2:c.1285G>C
NM_001195799.2:c.1162G>C
NM_001195800.2:c.781G>C
NM_001195803.2:c.904G>C

Pathogenic

• Met criteria codes: PM5 PS3 PM2 PP3 PP4 PS4_Supporting

• Not Met criteria codes: BS4 BS3 BS1 BS2 PVS1 BP5 BP7 BP2 BP3 BP4 BP1 PM3 PM1 PM4 PS2 PS1 PM6 BA1 PP1 PP2

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

Evidence submitted by expert panel

Familial Hypercholesterolemia VCEP

The NM_000527.5(LDLR):c.1285G>C (p.Val429Leu) variant is classified as Pathogenic for Familial Hypercholesterolemia by applying ACMG/AMP evidence codes PS3, PM2, PM5, PP3, PP4 and PS4_Supporting, as defined by the ClinGen Familial Hypercholesterolemia Expert Panel LDLR-specific variant curation guidelines (specification version 1.2) on 27 March 2023. The supporting evidence is as follows: PM2: This variant is absent from gnomAD (gnomAD v2.1.1). PP3: REVEL = 0.764. PM5: There is 1 variant in the same codon classified as Pathogenic by these guidelines, NM_000527.5(LDLR): c.1285G<A (p.Val429Met) (ClinVar ID: 3694). PS3: Level 1 assay: Heterologous cells (CHO), 125I-LDL and WB assays, 22% cell surface LDLR and binding and 10% uptake, PMID 25386756 (Etxebarria et al., 2014). Level 1 assay: Heterologous cells (CHO), 125I-LDL and WB assays, 15-30% LDLR activity, reduced mature protein, PMID 23021490 (Silva et al, 2012). ---- Overall, functional studies show an activity below 70% of wild-type, consistent with damaging effect. PS4_Supporting, PP4: Variant meets PM2 and is identified in at least 3 unrelated index cases (2 cases with DLCN score >=6 from PathWest Laboratory Medicine WA, Australia; 1 case with possible FH by Simon Broome criteria from Instituto Nacional de Saúde Dr. Ricardo Jorge, Portugal, PMID 17765246 (Bourbon et al., 2008).

Met criteria codes

• PM5: NM_000527.5(LDLR): c.1285G<A p.Val429Met (ClinVar ID: 3694) - Pathogenic by these guidelines There is 1 variant in the same codon classified as Pathogenic by these guidelines.
• PS3: Level 1 assay: Heterologous cells (CHO), 125I-LDL and WB assays, 22% cell surface LDLR and binding and 10% uptake. PMID: 25386756 // Level 1 assay: Heterologous cells (CHO), 125I-LDL and WB assays, 15-30% LDLR activity, reduced mature protein. PMID: 23021490. ---- Overall, functional studies (PMID: 25386756 and 23021490) show an activity below 70% of wild-type, so functional study is consistent with damaging effect.
• PM2: This variant is absent from gnomAD (gnomAD v20210610).
• PP3: REVEL = 0.764. It is above 0.75.
• PP4: Variant meets PM2 and is identified in 3 index cases who fulfill clinical criteria for FH from multiple labs (see PS4 for details), after alternative causes of high cholesterol were excluded.
• PS4_Supporting: Variant meets PM2 and is identified in at least 2 unrelated index cases (3 index cases total = 2 cases with DLCN criteria>=6 from PathWest Laboratory Medicine WA, Australia; 1 case with SB criteria of possible FH from Instituto Nacional de Saude Doutor, Portugal)/PMID:17765246 from lab Instituto Nacional de Saude Doutor, Portugal

Not Met criteria codes

• BS4: No instance of variant non-segregation with FH phenotype in at least 2 informative meiosis from at least 2 families with at least one unaffected relative (LDL-C <50th centile) who is positive for the variant.
• BS3: Level 1 assay: Heterologous cells (CHO), 125I-LDL and WB assays, 22% cell surface LDLR and binding and 10% uptake. PMID: 25386756 // Level 1 assay: Heterologous cells (CHO), 125I-LDL and WB assays, 15-30% LDLR activity, reduced mature protein. PMID: 23021490. ---- Overall, functional studies (PMID: 25386756 and 23021490) show an activity below 90% of wild-type, so functional study is consistent with damaging effect.
• BS1: This variant is absent from gnomAD (gnomAD v20210610).
• BS2: Variant not identified in at least 3 heterozygous/1 true homozygous well-phenotyped, normolipidemic, untreated, unrelated adults.
• PVS1: Missense variant and not in exon 1- not applicable.
• BP5: not applicable
• BP7: Missense variant - not applicable.
• BP2: Variant meets PM2 but is not identified in an index case with heterozygous or homozygous FH phenotype as well as LDLR variant, in trans, or APOB/PCSK9 variant classified as Pathogenic by these or general ACMG guidelines.
• BP3: not applicable
• BP4: REVEL: 0.764. Score is not below 0.50.
• BP1: Not applicable
• PM3: Variant meets PM2 but is not identified in an index case with heterozygous or homozygous FH phenotype as well as LDLR variant, in trans, or APOB/PCSK9 variant classified as Pathogenic by these or general ACMG guidelines.
• PM1: Missense at codon 406. PM2 is Met, but it is not exon 4 or any of the 60 Cys residues listed. Not applicable.
• PM4: Missense variant - not applicable.
• PS2: No de novo cases were identified.
• PS1: NM_000527.5(LDLR): c.1285G<T p.Val429Leu (ClinVar ID: 251767) - Pathogenic by these guidelines, but only after getting PM5 from variant NM_000527.5(LDLR): c.1285G<A p.Val429Met (ClinVar ID: 3694), so not met
• PM6: No de novo cases were identified.
• BA1: This variant is absent from gnomAD (gnomAD v20210610).
• PP1: Familial segregation/testing info was not completed/available. PathWest Laboratory Medicine WA, Australia and PMID ID: 17765246.
• PP2: Not applicable