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]

Variant: NM_000527.5(LDLR):c.1433G>A (p.Gly478Glu)

CA404085998

440642 (ClinVar)

Gene: LDLR (HGNC:3949)

Condition: hypercholesterolemia, familial (MONDO:0007750)

Inheritance Mode: Semidominant inheritance

UUID: 8b8852d5-2828-4890-8e43-8b948918b0e7

Approved on: 2022-01-31

Published on: 2022-07-11

HGVS expressions

NM_000527.5(LDLR):c.1433G>A (p.Gly478Glu)

NM_000527.5:c.1433G>A

NC_000019.10:g.11113609G>A

CM000681.2:g.11113609G>A

NC_000019.9:g.11224285G>A

CM000681.1:g.11224285G>A

NC_000019.8:g.11085285G>A

NG_009060.1:g.29229G>A

ENST00000558518.6:c.1433G>A

ENST00000252444.9:n.1687G>A

ENST00000455727.6:c.929G>A

ENST00000535915.5:c.1310G>A

ENST00000545707.5:c.1052G>A

ENST00000557933.5:c.1433G>A

ENST00000558013.5:c.1433G>A

ENST00000558518.5:c.1433G>A

ENST00000559340.1:n.154G>A

ENST00000560467.1:n.913G>A

NM_000527.4:c.1433G>A

NM_001195798.1:c.1433G>A

NM_001195799.1:c.1310G>A

NM_001195800.1:c.929G>A

NM_001195803.1:c.1052G>A

NM_001195798.2:c.1433G>A

NM_001195799.2:c.1310G>A

NM_001195800.2:c.929G>A

NM_001195803.2:c.1052G>A

Likely Pathogenic

PP4 PP3 PM5 PM2

PVS1 BS2 BS4 BS3 BS1 BP5 BP7 BP2 BP3 BP4 BP1 PS2 PS4 PS3 PS1 PP1 PP2 BA1 PM3 PM1 PM4 PM6

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_000527.4(LDLR):c.1433G>A (p.Gly478Glu) variant is classified as Likely pathogenic for Familial Hypercholesterolemia by applying evidence codes PM2, PM5, PP3 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: PM2 - This variant is absent from gnomAD (gnomAD v2.1.1), so PM2 is met. PM5 - 2 other missense variants in the same codon: (1) NM_000527.5(LDLR):c.1432G>A (p.Gly478Arg) - 1 star, Conflicting interpretations of pathogenicity: Likely pathogenic(8);Pathogenic(1);Uncertain significance(4) - Pathogenic by these guidelines (FH VCEP training Aug 2021) (2) NM_000527.5(LDLR):c.1432G>T (p.Gly478Trp) - 1 star, VUS in ClinVar - VUS by these guidelines --- there is 1 Pathogenic variant in the same codon, so PM5 is met. PP3 - REVEL = 0.984. It is above 0.75, so PP3 is met. PP4 - variant meets PM2 and was identified in 1 index case who fulfills Simon-Broome criteria from Cardiovascular Research Group,Instituto Nacional de Saude Doutor Ricardo Jorge, so PP4 is met

PP4

variant meets PM2 and was identified in 1 index case who fulfills Simon-Broome criteria from Cardiovascular Research Group,Instituto Nacional de Saude Doutor Ricardo Jorge. -- so PP4 is met

PP3

REVEL = 0.984. It is above 0.75, so PP3 is met

PM5

2 other missense variants in the same codon: (1) NM_000527.5(LDLR):c.1432G>A (p.Gly478Arg) - 1 star, Conflicting interpretations of pathogenicity: Likely pathogenic(8);Pathogenic(1);Uncertain significance(4) in ClinVar - Pathogenic by these guidelines (FH VCEP training Aug 2021) (2) NM_000527.5(LDLR):c.1432G>T (p.Gly478Trp) - 1 star, VUS in ClinVar - VUS by these guidelines 1 Pathogenic variant in the same codon, so PM5 is met

PM2

This variant is absent from gnomAD (gnomAD v2.1.1), so PM2 is met

PVS1

variant is missense and not in initiation codon, so PVS1 is not met

BS2

not identified in normolipidemic individuals, 0/92 non-FH individuals from Cardiovascular Research Group,Instituto Nacional de Saude Doutor Ricardo Jorge, so BS2 is not met

BS4

no segregation data

BS3

there are no published functional studies for this variant

BS1

This variant is absent from gnomAD (gnomAD v2.1.1), so not met

BP5

not applicable

BP7

variant is missense, so BP7 is not met

BP2

not identified in index cases with other variants

BP3

not applicable

BP4

REVEL = 0.984. It is not below 0.5, so BP4 is not met

BP1

not applicable

PS2

no de novo occurrence

PS4

variant meets PM2 and was identified in 1 index case who fulfills Simon-Broome criteria from Cardiovascular Research Group,Instituto Nacional de Saude Doutor Ricardo Jorge. -- not enough, so not met

PS3

there are no published functional studies for this variant

PS1

no other missense variant leads to the same amino acid change, so PS1 is not met

PP1

no segregation data

PP2

not applicable

BA1

This variant is absent from gnomAD (gnomAD v2.1.1), so not met

PM3

not identified in index cases with other variants

PM1

variant is missense and meets PM2, but it is not in exon 4 and does not alter Cys, so PM1 is not met.

PM4

variant is missense, so PM4 is not met

PM6

no de novo occurrence

Curation History

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