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]

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Variant: NM_000527.5(LDLR):c.2389+2T>G

CA10585839

252302 (ClinVar)

Gene: LDLR

Condition: hypercholesterolemia, familial

Inheritance Mode: Semidominant inheritance

Link to MONDO

UUID: 22e706c7-ea28-4ea2-9c69-0d0aaf27be47

HGVS expressions

NM_000527.5:c.2389+2T>G

NM_000527.5(LDLR):c.2389+2T>G

NC_000019.10:g.11128087T>G

CM000681.2:g.11128087T>G

NC_000019.9:g.11238763T>G

CM000681.1:g.11238763T>G

NC_000019.8:g.11099763T>G

NG_009060.1:g.43707T>G

ENST00000558518.6:c.2389+2T>G

ENST00000252444.9:n.2643+2T>G

ENST00000455727.6:c.1885+2T>G

ENST00000535915.5:c.2266+2T>G

ENST00000545707.5:c.1855+2T>G

ENST00000557933.5:c.2389+2T>G

ENST00000558013.5:c.2389+2T>G

ENST00000558518.5:c.2389+2T>G

ENST00000560628.1:n.108+433T>G

NM_000527.4:c.2389+2T>G

NM_001195798.1:c.2389+2T>G

NM_001195799.1:c.2266+2T>G

NM_001195800.1:c.1885+2T>G

NM_001195803.1:c.1855+2T>G

NM_001195798.2:c.2389+2T>G

NM_001195799.2:c.2266+2T>G

NM_001195800.2:c.1885+2T>G

NM_001195803.2:c.1855+2T>G

Pathogenic

PVS1_Strong PP1_Moderate PP4 PM2 PS4_Supporting

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

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.2389+2T>G variant is classified as Pathogenic for Familial Hypercholesterolemia by applying evidence codes PVS1_Strong, PP1_moderate, PM2, PP4 and PS4_Supporting, 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: PVS1_strong - variant is at +2 donor splice site, and is predicted to lead to exon 16 skipping. Exon 16 is in frame, so PVS1_Strong is met. PP1_moderate - variant segregates with FH phenotype in 5 relatives from Robarts Research Institute, so PP1_Moderate is met. PM2 - This variant was not identified in gnomAD (gnomAD v2.1.1), so PM2 is met. PS4_Supporting - variant meets PM2 and is identified in 3 unrelated index cases, after alternative causes of hypercholesterolemia were excluded, from different labs (1 with DLCN >=6 from Robarts Research Institute, 1 with possible FH according to Simon-Broome criteria from PMID 17539906 (UK) and 1 with DLCN >=6 from PMID 33418990 (Russia)), so PS4_Supporting is met. PP4 - variant meets PM2 and is identified in 3 unrelated index cases from different labs (see PS4 for details), so PP4 is met.

PVS1_Strong

variant is at +2 donor splice site, and is predicted to lead to exon 16 skipping. Exon 16 is in frame, so PVS1_Strong is met

PP1_Moderate

variant segregates with FH phenotype in 5 relatives from Robarts Research Institute: all 5 relatives have the variant and LDL-C >75th percentile. so PP1_Moderate is met

PP4

variant meets PM2 and is identified in - 1 index case with DLCN >=6 from Robarts Research Institute - 1 index case with possible FH according to Simon-Broome criteria from PMID 17539906 (UK). - 1 index case with DLCN >=6 from PMID 33418990 (Russia) so PP4 is met

PM2

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

PS4_Supporting

PS2

no de novo occurrence was identified

PS3

There are no published functional studies on the variant

PS1

variant is intronic, so not applicable

BP2

no index cases with more than 1 variant were identified

BP3

not applicable

BP4

variant meets PVS1, so not met

BP1

not applicable

BP5

not applicable

BP7

variant is intronic, so not applicable

BA1

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

PP3

variant meets PVS1, so not met

PP2

not applicable

PM3

no index cases with more than 1 variant were identified

PM1

variant is intronic, so not applicable

PM5

variant is intronic, so not applicable

PM4

variant is intronic, so not applicable

PM6

no de novo occurrence was identified

BS2

not identified in normolipidemic individuals: 0/1000 controls from Robarts Research Institute, so not met

BS4

no non-segregation was identified

BS3

There are no published functional studies on the variant

BS1

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

Approved on: 2022-08-28

Published on: 2022-08-28

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