Evidence Repository - Clinical Genome Resources

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Variant: NM_000527.5(LDLR):c.2416dup (p.Val806fs)

CA040715

252330 (ClinVar)

Gene: LDLR

Condition: hypercholesterolemia, familial

Inheritance Mode: Semidominant inheritance

Link to MONDO

UUID: 3c40ab01-a309-4764-bdc2-4fe4a273586c

HGVS expressions

NM_000527.5:c.2416dup

NM_000527.5(LDLR):c.2416dup (p.Val806fs)

NC_000019.10:g.11129539dup

CM000681.2:g.11129539dup

NC_000019.9:g.11240215dup

CM000681.1:g.11240215dup

NC_000019.8:g.11101215dup

NG_009060.1:g.45159dup

ENST00000558518.6:c.2416dup

ENST00000252444.9:n.2670dup

ENST00000455727.6:c.1912dup

ENST00000535915.5:c.2293dup

ENST00000545707.5:c.1882dup

ENST00000557933.5:c.2478dup

ENST00000558013.5:c.2416dup

ENST00000558518.5:c.2416dup

ENST00000560628.1:n.108+1885dup

NM_000527.4:c.2416dup

NM_001195798.1:c.2416dup

NM_001195799.1:c.2293dup

NM_001195800.1:c.1912dup

NM_001195803.1:c.1882dup

NM_001195798.2:c.2416dup

NM_001195799.2:c.2293dup

NM_001195800.2:c.1912dup

NM_001195803.2:c.1882dup

Pathogenic

PVS1 PS4 PP4 PP1_Strong PM2

BS2 BS4 BS3 BS1 BP5 BP7 BP2 BP3 BP4 BP1 PS2 PS3 PS1 BA1 PP3 PP2 PM6 PM3 PM1 PM4 PM5

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 1.1

PDF

Criteria Specification Approval History

Criteria Specifications for this VCEP

Evidence submitted by expert panel

Familial Hypercholesterolemia VCEP

The NM_000527.5(LDLR):c.2416dup (p.Val806fs) variant is classified as Pathogenic for Familial Hypercholesterolemia by applying evidence codes PVS1, PP1_Strong, PS4, PM2 and PP4 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: PVS1 - variant is frameshift upstream of amino acid 830, so PVS1 is met. PP1_strong - variant segregates with the FH phenotype in - 1 informative meiosis from Cardiovascular Research Group,Instituto Nacional de Saude Doutor Ricardo Jorge: 1 relative with the phenotype has the variant; - 7 informative meiosis from Molecular Genetics Laboratory (Centre for Cardiovascular Surgery and Transplantation): data from 4 families: 6 relatives with the phenotype have the variant plus 1 relative without the phenotype does not have the variant; 8 informative meiosis support co-segregation, so PP1_Strong is met. PS4 - variant meets PM2 and was identified in - 6 unrelated index cases with DLCN>6 from Roberts Research Institute, Canada; - 1 index case with DLCN>6 from COLOR, USA; - 2 unrelated index cases who fulfill SB criteria of possible FH from Cardiovascular Research Group,Instituto Nacional de Saude Doutor Ricardo Jorge, Portugal; - 5 unrelated index cases who fulfill SB criteria of possible FH from Molecular Genetics Laboratory (Centre for Cardiovascular Surgery and Transplantation), Czech Republic; 14 cases, so PS4 is met PM2 - This variant was not identified in gnomAD (gnomAD v2.1.1), so PM2 is met. PP4 - variant meets PM2 and was identified in 14 unrelated index cases from different labs (please see PS4 for details), so PP4 is met.

PVS1

variant is frameshift upstream of amino acid 830, so PVS1 is met

PS4

variant meets PM2. identified in - 6 unrelated index cases with DLCN>6 from Roberts Research Institute, Canada; - 1 index case with DLCN>6 from COLOR, USA; - 2 unrelated index cases who fulfill SB criteria of possible FH from Cardiovascular Research Group,Instituto Nacional de Saude Doutor Ricardo Jorge, Portugal; - 5 unrelated index cases who fulfill SB criteria of possible FH from Molecular Genetics Laboratory (Centre for Cardiovascular Surgery and Transplantation), Czech Republic; 14 cases, so PS4 is met

PP4

variant meets PM2. identified in - 6 unrelated index cases with DLCN>6 from Roberts Research Institute, Canada; - 1 index case with DLCN>6 from COLOR, USA; - 2 unrelated index cases who fulfill SB criteria of possible FH from INSA (Cardiovascular Research Group,Instituto Nacional de Saude Doutor Ricardo Jorge), Portugal; - 5 unrelated index cases who fulfill SB criteria of possible FH from Molecular Genetics Laboratory (Centre for Cardiovascular Surgery and Transplantation), Czech Republic; so PP4 is met

PP1_Strong

variant segregates with the FH phenotype in - 1 informative meiosis from Cardiovascular Research Group,Instituto Nacional de Saude Doutor Ricardo Jorge: 1 relative with the phenotype has the variant; - 7 informative meiosis from Molecular Genetics Laboratory (Centre for Cardiovascular Surgery and Transplantation): data from 4 families: 6 relatives with the phenotype have the variant plus 1 relative without the phenotype does not have the variant 8 informative meiosis support co-segregation, so PP1_Strong is met

PM2

This variant was not identified in gnomAD (gnomAD v2.1.1), so PM2 is met

BS2

not identified in normolipidemic individuals: 0/188 non-FH alleles from Cardiovascular Research Group,Instituto Nacional de Saude Doutor Ricardo Jorge, so BS2 is not met

BS4

there is lack of segregation between the FH phenotype and the variant in: - 2 informative meiosis from 1 family from INSA (Cardiovascular Research Group,Instituto Nacional de Saude Doutor Ricardo Jorge): 2 relatives with the phenotype do not have the variant. there is only data from 1 family, so BS4 is not met

BS3

only functional studies in compound heterozygote cells, so not met

BS1

This variant was not identified in gnomAD (gnomAD v2.1.1)

BP5

not applicable

BP7

variant is frameshift, not applicable

BP2

variant was identified in 1 index case with LDLc = 4.3 mmol/l (16y), who also has NM_000527.4(LDLR):c.-120C>T - 1 star, conflicting classifications in ClinVar, VUS by these guidelines, in trans, from Molecular Genetics Laboratory (Centre for Cardiovascular Surgery and Transplantation) --- the other variant is not classified as Pathogenic or Likely pathogenic, so not met

BP3

not applicable

BP4

variant meets PVS1, so not applicable

BP1

not applicable

PS2

no de novo occurrence

PS3

only functional studies in compound heterozygote cells, so not met

PS1

variant is frameshift, not applicable

BA1

This variant was not identified in gnomAD (gnomAD v2.1.1)

PP3

variant meets PVS1, so not applicable

PP2

not applicable

PM6

no de novo occurrence

PM3

variant meets PM2 and was identified in: - 1 index case with LDL-C 10.35 mmol/l, who also has NM_000527.5(LDLR):c.326G>A (p.Cys109Tyr) - 2 stars, P/LP in ClinVar, Likely pathogenic by these guidelines in trans, from Roberts Research Institute, but phenotype is not clearly homozygous (not above 13mmol/L), so not met --- the phenotype is not clearly homozygous FH, so not met

PM1

variant is not missense, so not applicable

PM4

variant is frameshift, not applicable

PM5

variant is frameshift, not applicable

Approved on: 2022-08-28

Published on: 2022-08-28

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