Evidence Repository
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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  • See Evidence submitted by expert panel for details.

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

CA10584820

251106 (ClinVar)

Gene: LDLR
Condition: hypercholesterolemia, familial
Inheritance Mode: Semidominant inheritance
Link to MONDO
UUID: 4daee3a2-127a-4b15-b576-c9807a69f926

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 4
PM2 PM5_Strong PP4 PP3
Not Met criteria codes 22
PM4 PM1 PM3 PM6 PVS1 BS2 BS3 BS4 BS1 BP7 BP5 BP3 BP2 BP4 BP1 PS4 PS1 PS3 PS2 BA1 PP1 PP2

Evidence Links 0

Expert Panel

Criteria Specification Information

Criteria Specifications for this VCEP
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
PM2
No population data was found for this variant in gnomAD (gnomAD v2.1.1).
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.
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
Not Met criteria codes
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
PVS1
Missense variant, PVS1 Not Met
BS2
no unaffected individuals identified with the variant, so BS2 is Not Met
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).
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
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
BA1
No population data was found for this variant in gnomAD (gnomAD v2.1.1).
PP1
no family members were tested, so PP1 is Not Met
PP2
Not applicable
Approved on: 2021-06-07
Published on: 2021-06-24
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