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

CA10585839

252302 (ClinVar)

Gene: LDLR

Condition: hypercholesterolemia, familial

Inheritance Mode: Semidominant inheritance

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

Approved on: 2022-08-28

Published on: 2022-08-28

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

• Met criteria codes: PVS1_Strong PP4 PP1_Moderate PS4_Supporting PM2

• Not Met criteria codes: BS4 BS3 BS1 BS2 BP5 BP7 BP2 BP3 BP4 BP1 PS2 PS3 PS1 BA1 PP3 PP2 PM3 PM1 PM5 PM4 PM6

Expert Panel

Familial Hypercholesterolemia VCEP

Criteria Specification Information

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.

Met criteria codes

• 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
• 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
• 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
• PS4_Supporting: 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) 3 cases, so PS4_Supporting is met
• PM2: This variant was not identified in gnomAD (gnomAD v2.1.1), so PM2 is met

Not Met criteria codes

• 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)
• BS2: not identified in normolipidemic individuals: 0/1000 controls from Robarts Research Institute, so not met
• BP5: not applicable
• BP7: 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
• PS2: no de novo occurrence was identified
• PS3: There are no published functional studies on the variant
• PS1: 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