Variant: NM_000527.5(LDLR):c.268G>T (p.Asp90Tyr)

CA10584820

251106 (ClinVar)

Gene: LDLR

Condition: hypercholesterolemia, familial

Inheritance Mode: Semidominant inheritance

UUID: 4daee3a2-127a-4b15-b576-c9807a69f926

Approved on: 2021-06-07

Published on: 2021-06-24

HGVS expressions

NM_000527.5:c.268G>T
NM_000527.5(LDLR):c.268G>T (p.Asp90Tyr)
ENST00000558518.6:c.268G>T
ENST00000252444.9:n.522G>T
ENST00000455727.6:c.268G>T
ENST00000535915.5:c.190+2396G>T
ENST00000545707.5:c.268G>T
ENST00000557933.5:c.268G>T
ENST00000557958.1:n.354G>T
ENST00000558013.5:c.268G>T
ENST00000558518.5:c.268G>T
NM_000527.4:c.268G>T
NM_001195798.1:c.268G>T
NM_001195799.1:c.190+2396G>T
NM_001195800.1:c.268G>T
NM_001195803.1:c.268G>T
NM_001195798.2:c.268G>T
NM_001195799.2:c.190+2396G>T
NM_001195800.2:c.268G>T
NM_001195803.2:c.268G>T
NC_000019.10:g.11102741G>T
CM000681.2:g.11102741G>T
NC_000019.9:g.11213417G>T
CM000681.1:g.11213417G>T
NC_000019.8:g.11074417G>T
NG_009060.1:g.18361G>T

Likely Pathogenic

• Met criteria codes: PP4 PP3 PM5_Strong PM2

• Not Met criteria codes: PVS1 PS4 PS1 PS3 PS2 PP1 PP2 PM4 PM1 PM3 PM6 BA1 BS3 BS4 BS1 BS2 BP7 BP5 BP3 BP2 BP4 BP1

Expert Panel

Familial Hypercholesterolemia VCEP

Criteria Specification Information

Evidence submitted by expert panel

Familial Hypercholesterolemia VCEP

The NM_000527.5(LDLR):c.268G>T (p.Asp90Tyr) variant is classified as Likely pathogenic for Familial Hypercholesterolemia by applying evidence codes (PM5_Strong, PM2, PP3 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: PM5_Strong - Four more missense variants described in same codon: --- 3 variants classified as Pathogenic, so PM5_Strong is Met. PM2 - No population data was found for this variant in gnomAD (gnomAD v2.1.1). PM5 - Four more missense variants described in same codon, 3 variants classified as Pathogenic, so PM5 is Met. PP3 - REVEL = 0.958. It is above 0.75, so PP3 is Met. PP4 - Variant meets PM2. Identified in 1 index case who fulfills Simon-Broome criteria from Center of molecular biology and gene therapy.

Met criteria codes

• PP4: Variant meets PM2. Identified in 1 index case who fulfills Simon-Broome criteria (high LDL value, family history of high early CVD = possible FH) from Center of molecular biology and gene therapy ---- PP4 is Met
• PP3: REVEL = 0.958. It is above 0.75, so PP3 is Met
• PM5_Strong: Four more missense variants described in same codon: (1)NM_000527.5(LDLR):c.268G>A (p.Asp90Asn) (ClinVar ID 251105) - Pathogenic by these guidelines (2)NM_000527.4(LDLR):c.269A>C (p.Asp90Ala) (ClinVar ID 440555) - Likely pathogenic by these guidelines (3)NM_000527.5(LDLR):c.269A>G (p.Asp90Gly) (ClinVar ID 226313) - Pathogenic by these guidelines (4)NM_000527.5(LDLR):c.270T>A (p.Asp90Glu) (ClinVar ID 251107) - Pathogenic by these guidelines --- 3 variants classified as Pathogenic, so PM5_Strong is Met.
• PM2: No population data was found for this variant in gnomAD (gnomAD v2.1.1).

Not Met criteria codes

• PVS1: Missense variant, PVS1 Not Met
• PS4: Variant meets PM2. Identified in 1 index case from Center of molecular biology and gene therapy who fulfills Simon-Broome criteria for FH. not enough evidence to meet PS4. ---- PS4 is Not Met
• PS1: No variant described that leads to the same amino acid change, so PS1 is Not Met
• PS3: no functional assays performed, not applicable
• PS2: no de novo cases were identified, so PS2 is Not Met
• PP1: no family members were tested, so PP1 is Not Met
• PP2: Not applicable
• PM4: Missense variant, not applicable
• PM1: Missense at codon 90. PM2 is Met, but it is not exon 4 or any of the 60 Cys residues listed, so PM1 is Not Met
• PM3: not identified in individuals with other variants, so PM3 is Not Met
• PM6: no de novo cases were identified, so PM6 is Not Met
• BA1: No population data was found for this variant in gnomAD (gnomAD v2.1.1).
• BS3: no functional assays performed, not applicable
• BS4: no family members were tested, so BS4 is Not Met
• BS1: No population data was found for this variant in gnomAD (gnomAD v2.1.1).
• BS2: no unaffected individuals identified with the variant, so BS2 is Not Met
• BP7: Missense variant, so BP7 is not applicable
• BP5: Not applicable
• BP3: Not applicable
• BP2: not identified in individuals with other variants, so BP2 is Not Met
• BP4: REVEL = 0.958. It is not below 0.15 and PP3 is Met, so BP4 is Not Met
• BP1: Not applicable