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.1060+10G>C

Curation Version - 1.0
Curation History
JSON LD for Version 1.0

CA031460

226709 (ClinVar)

Gene: LDLR

Condition: hypercholesterolemia, familial

Inheritance Mode: Semidominant inheritance

Link to MONDO

UUID: be6aeb00-7d31-427c-a316-d2d916965de3

Approved on: 2021-06-23

Published on: 2021-06-24

HGVS expressions

NM_000527.5:c.1060+10G>C

NM_000527.5(LDLR):c.1060+10G>C

ENST00000558518.6:c.1060+10G>C

ENST00000252444.9:n.1314+10G>C

ENST00000455727.6:c.556+10G>C

ENST00000535915.5:c.937+10G>C

ENST00000545707.5:c.679+10G>C

ENST00000557933.5:c.1060+10G>C

ENST00000558013.5:c.1060+10G>C

ENST00000558518.5:c.1060+10G>C

ENST00000560173.1:n.59+10G>C

ENST00000560467.1:n.541-733G>C

NM_000527.4:c.1060+10G>C

NM_001195798.1:c.1060+10G>C

NM_001195799.1:c.937+10G>C

NM_001195800.1:c.556+10G>C

NM_001195803.1:c.679+10G>C

NM_001195798.2:c.1060+10G>C

NM_001195799.2:c.937+10G>C

NM_001195800.2:c.556+10G>C

NM_001195803.2:c.679+10G>C

NC_000019.10:g.11110781G>C

CM000681.2:g.11110781G>C

NC_000019.9:g.11221457G>C

CM000681.1:g.11221457G>C

NC_000019.8:g.11082457G>C

NG_009060.1:g.26401G>C

Benign

BA1 BS2 BP4 BP2

PS2 PS4 PS3 PS1 PP4 PP1 PP3 PP2 PM6 PM2 PM1 PM4 PM5 PM3 PVS1 BS4 BS3 BS1 BP3 BP1 BP5 BP7

Evidence Links 0

Expert Panel

Familial Hypercholesterolemia VCEP

Criteria Specification Information

Criteria Specifications for this VCEP

Evidence submitted by expert panel

Familial Hypercholesterolemia VCEP

The NM_000527.5(LDLR):c.1060+10G>C variant is classified as Benign for Familial Hypercholesterolemia by applying evidence codes BA1, BS2, BP2 and BP4 as defined by the ClinGen Familial Hypercholesterolemia Expert Panel LDLR-specific variant curation guidelines (https://doi.org/10.1101/2021.03.17.21252755). The supporting evidence is as follows: BA1 - FAF = 0.4446 (44.46%) in European non-Finnish exomes (gnomAD v2.1.1). BS2 - observed in homozygosity in 155 normolipidemic individuals (118 from Color, 22 from INSA, 15 from Western University), as well as in heterozygosity in 376 normolipidemic individuals (297 from Color, 46 INSA, 33 from Western University). BP2 - Variant co-occurs with a Pathogenic LDLR variant (classified by these guidelines) in 6 individuals with a clear heterozygous FH phenotype (LDL-C <8 mmol/L). BP4 - no REVEL, splicing evaluation required. No functional studies variant not on splicing limits, so BP4 is met.

BA1

FAF = 0.4446 (44.46%) in European non-Finnish exomes (gnomAD v2.1.1)

BS2

observed in homozygosity in 155 normolipidemic individuals (118 from Color, 22 from INSA, 15 from Western University), as well as in heterozygosity in 376 normolipidemic individuals (297 from Color, 46 INSA, 33 from Western University)

BP4

no REVEL, splicing evaluation required. No functional studies variant not on splicing limits, so BP4 is met

BP2

Variant co-occurs with a Pathogenic LDLR variant (classified by these guidelines) in 6 individuals with a clear heterozygous FH phenotype (LDL-C <8 mmol/L)

PS2

No de novo data available

PS4

Does not meet PM2 caveat

PS3

No functional data available

PS1

NA; intronic

PP4

PM2 caveat not met

PP1

No segregation data available

PP3

no REVEL, splicing evaluation required. No functional studies variant not on splicing limits

PP2

PM6

No de novo data available

PM2

PopMax MAF = 0.4917 (49.17%) in European Finnish (gnomAD v2.1.1)

PM1

Not in exon 4 or at a CYS

PM4

NA; intronic

PM5

NA; intronic

PM3

Does not meet PM2 caveat

PVS1

NA; outside canonical splice sites

BS4

No segregation data available

BS3

No functional data available

BS1

BA1 is met

BP3

BP1

BP5

BP7

NA; intronic

Curation History

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