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.805G>A (p.Gly269Ser)

Curation Version - 1.1
Curation History
JSON LD for Version 1.1

CA404080212

430763 (ClinVar)

Gene: LDLR

Condition: hypercholesterolemia, familial

Inheritance Mode: Semidominant inheritance

Link to MONDO

UUID: e14355e7-d494-48d0-a484-a004e21ce104

Approved on: 2021-12-13

Published on: 2022-07-11

HGVS expressions

NM_000527.5:c.805G>A

NM_000527.5(LDLR):c.805G>A (p.Gly269Ser)

NC_000019.10:g.11106675G>A

CM000681.2:g.11106675G>A

NC_000019.9:g.11217351G>A

CM000681.1:g.11217351G>A

NC_000019.8:g.11078351G>A

NG_009060.1:g.22295G>A

ENST00000558518.6:c.805G>A

ENST00000252444.9:n.1059G>A

ENST00000455727.6:c.314-717G>A

ENST00000535915.5:c.682G>A

ENST00000545707.5:c.424G>A

ENST00000557933.5:c.805G>A

ENST00000558013.5:c.805G>A

ENST00000558518.5:c.805G>A

ENST00000558528.1:n.320G>A

ENST00000560467.1:n.405G>A

NM_000527.4:c.805G>A

NM_001195798.1:c.805G>A

NM_001195799.1:c.682G>A

NM_001195800.1:c.314-717G>A

NM_001195803.1:c.424G>A

NM_001195798.2:c.805G>A

NM_001195799.2:c.682G>A

NM_001195800.2:c.314-717G>A

NM_001195803.2:c.424G>A

Uncertain Significance

PP4 PM2

PS2 PS4 PS3 PS1 BP5 BP7 BP2 BP3 BP4 BP1 BA1 PP1 PP3 PP2 PVS1 PM3 PM1 PM4 PM5 PM6 BS2 BS4 BS3 BS1

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.805G>A (p.Gly269Ser) variant is classified as Uncertain significance - insufficient evidence for Familial Hypercholesterolemia by applying evidence codes (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: PM2 - This variant is absent from gnomAD (gnomAD v2.1.1), so PM2 is met. PP4 - Variant meets PM2 and was identified in 1 index case who fulfills DLCN criteria of probable FH from U4M - Lille University & CHRU Lille, Université de Lille - CHRU de Lille (SCV000583742.1 in ClinVar), so PP4 is met.

PP4

Variant meets PM2 and was identified in 1 index case who fulfills DLCN criteria of probable FH from U4M - Lille University & CHRU Lille, Université de Lille - CHRU de Lille (SCV000583742.1 in ClinVar), so PP4 is met

PM2

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

PS2

no de novo occurrence identified

PS4

PS3

There are no published functional studies, so PS3 is not met

PS1

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

BP5

not applicable

BP7

variant is missense, so not applicable

BP2

There is no case data, so not met

BP3

not applicable

BP4

REVEL = 0.743. it is not below 0.5, so BP4 is not met.

BP1

Not applicable

BA1

This variant is absent from gnomAD (gnomAD v2.1.1), so BA1 is not met

PP1

there is no segregation data

PP3

REVEL = 0.743. it is not above 0.75, so splicing is needed. A) not on limits B) it does not create GT C) there is a GT nearby MES scores: variant cryptic = -2.15, wt cryptic = -4.54, authentic donor = 8.27. Scores are negative, so they are not used, so PP3 is not met

PP2

Not applicable

PVS1

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

PM3

There is no case data, so not met

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 not applicable

PM5

one other missense variant in the same codon: - NM_000527.5(LDLR):c.806G>A (p.Gly269Asp) - 1 star, Conflicting interpretations of pathogenicity: Benign(1);Likely benign(8);Likely pathogenic(1);Uncertain significance(1) - Likely benign classified by the FH VCEP so PM5 is not met

PM6

no de novo occurrence identified

BS2

Variant was not searched in normolipidemic individuals, so not met

BS4

there is no segregation data

BS3

There are no published functional studies, so BS3 is not met

BS1

This variant is absent from gnomAD (gnomAD v2.1.1), so BS1 is not met

Curation History

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