Variant: NM_000527.4(LDLR):c.1061-?_1845+?del

265901 (ClinVar)

Gene: LDLR

Condition: hypercholesterolemia, familial

Inheritance Mode: Semidominant inheritance

UUID: 4ec3a403-6eee-4822-846f-2a5dbf6e9d6d

HGVS expressions

NM_000527.4:c.1061-?_1845+?del
NM_000527.4(LDLR):c.1061-?_1845+?del

Pathogenic

• Met criteria codes: PVS1 PP1_Moderate PP4 PM2

• Not Met criteria codes: BA1 BP4 BP1 BP2 BP3 BP5 BP7 BS2 BS3 BS1 BS4 PP3 PP2 PS2 PS4 PS1 PS3 PM3 PM4 PM1 PM5 PM6

Expert Panel

Familial Hypercholesterolemia VCEP

Criteria Specification Information

Evidence submitted by expert panel

Familial Hypercholesterolemia VCEP

The NM_000527.4(LDLR):c.1061-?_1845+?del variant is classified as Pathogenic for Familial Hypercholesterolemia by applying evidence codes (PVS1, PP1_Moderate, PM2 and PP4) 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 - Deletion of exons 8 through 12, predicted to lead to out-of frame consequence, so PVS1 is Met. PP1_moderate - variant segregates with FH phenotype in 5 informative meiosis in 1 family from Cardiovascular Research Group,Instituto Nacional de Saude Doutor Ricardo Jorge. PM2 - No population data was found for this variant in gnomAD (gnomAD SVs v2.1). PP4 - Variant meets PM2. Variant identified in 1 index case who fulfils SB criteria for FH from Cardiovascular Research Group,Instituto Nacional de Saude Doutor Ricardo Jorge.

Met criteria codes

• PVS1: Deletion of exons 8 through 12, predicted to lead to out-of frame consequence, so PVS1 is Met
• PP1_Moderate: variant segregates with FH phenotype in 5 informative meiosis in 1 family from Cardiovascular Research Group,Instituto Nacional de Saude Doutor Ricardo Jorge: 4 affected family members have the variant, plus 1 unaffected family member does not have the variant ---- PP1_Moderate is Met
• PP4: Variant meets PM2. Variant identified in 1 index case who fulfils SB criteria for FH from Cardiovascular Research Group,Instituto Nacional de Saude Doutor Ricardo Jorge.
• PM2: No population data was found for this variant in gnomAD (gnomAD SVs v2.1)

Not Met criteria codes

• BA1: No population data was found for this variant in gnomAD (gnomAD SVs v2.1)
• BP4: PVS1 is Met, so BP4 is not applicable
• BP1: Not applicable
• BP2: not identified in individuals with other variants, so BP2 is Not Met
• BP3: Not applicable
• BP5: Not applicable
• BP7: Copy-number variant (large deletion), so BP7 is not applicable
• BS2: no unaffected individuals identified with the variant, so BS2 is Not Met
• BS3: no functional assays performed, not applicable
• BS1: No population data was found for this variant in gnomAD (gnomAD SVs v2.1)
• BS4: no lack of segregation was identified, so BS4 is Not Met
• PP3: PVS1 is Met, so PP3 is not applicable
• PP2: Not applicable
• PS2: no de novo cases were identified, so PS2 is Not Met
• PS4: Variant meets PM2. Variant identified in 1 index case who fulfils SB criteria for FH from Cardiovascular Research Group,Instituto Nacional de Saude Doutor Ricardo Jorge. -- not enough for PS4, so not met
• PS1: Copy-number variant (large deletion), PS1 not applicable
• PS3: no functional assays performed, not applicable
• PM3: not identified in individuals with other variants, so PM3 is Not Met
• PM4: Deletion of exons 8 through 12 (predicted to lead to out-of frame consequence), so PM4 is Not Met
• PM1: Large deletion, so PM1 is not applicable
• PM5: Copy-number variant (large deletion), PM5 not applicable
• PM6: no de novo cases were identified, so PM6 is Not Met

Approved on: 2021-07-01

Published on: 2021-07-01