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.693C>G (p.Cys231Trp)

CA10585085

251400 (ClinVar)

Gene: LDLR
Condition: hypercholesterolemia, familial
Inheritance Mode: Semidominant inheritance
Link to MONDO
UUID: 85e34844-d082-4855-ae9a-838120d2675c
Approved on: 2021-06-07
Published on: 2021-06-24

HGVS expressions

NM_000527.5:c.693C>G
NM_000527.5(LDLR):c.693C>G (p.Cys231Trp)
ENST00000558518.6:c.693C>G
ENST00000252444.9:n.947C>G
ENST00000455727.6:c.314-1793C>G
ENST00000535915.5:c.570C>G
ENST00000545707.5:c.314-966C>G
ENST00000557933.5:c.693C>G
ENST00000558013.5:c.693C>G
ENST00000558518.5:c.693C>G
ENST00000560467.1:n.293C>G
NM_000527.4:c.693C>G
NM_001195798.1:c.693C>G
NM_001195799.1:c.570C>G
NM_001195800.1:c.314-1793C>G
NM_001195803.1:c.314-966C>G
NM_001195798.2:c.693C>G
NM_001195799.2:c.570C>G
NM_001195800.2:c.314-1793C>G
NM_001195803.2:c.314-966C>G
NC_000019.10:g.11105599C>G
CM000681.2:g.11105599C>G
NC_000019.9:g.11216275C>G
CM000681.1:g.11216275C>G
NC_000019.8:g.11077275C>G
NG_009060.1:g.21219C>G

Likely Pathogenic

Met criteria codes 5
PS4_Supporting PP4 PP3 PM1 PM2
Not Met criteria codes 21
BA1 BS2 PVS1 BS4 BS3 BS1 BP2 BP3 BP4 BP1 BP5 BP7 PS2 PS1 PS3 PP1 PP2 PM3 PM4 PM5 PM6

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.693C>G (p.Cys231Trp) variant is classified as Likely pathogenic for Familial Hypercholesterolemia by applying evidence codes (PM1, PM2, PP3, 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: PM1 - Missense at codon 231. PM2 is Met and Cys231 is one of the 60 Cys residues listed, so PM1 is Met. PM2 - No population data was found for this variant in gnomAD (gnomAD v2.1.1). PP3 - REVEL = 0.708. It is not above 0.75, splicing evaluation is required. Functional data on splicing not available. A) variant located -3 to +6 from canonical donor site MES scores: canonical site variant = 5.84; canonical site wt = 7.67. Ratio variant/wt canonical: 5.84/7.67 = 0.761. --- ratio is below 0.8, so PP3 is Met. PP4 - Variant meets PM2. Variant identified in at least 3 unrelated index cases with Simon-Broome criteria for FH from different labs. PS4_supporting - Variant meets PM2. Variant identified in at least 3 unrelated index cases with Simon-Broome criteria for FH from different labs.
Met criteria codes
PS4_Supporting
Variant meets PM2. Variant identified in at least 3 unrelated index cases with Simon-Broome criteria for FH (1 from Ambry Genetics and 2 from Cardiovascular Research Group,Instituto Nacional de Saude Doutor Ricardo Jorge) --- PS4_Supporting is Met
PP4
Variant meets PM2. Variant identified in at least 3 unrelated index cases with Simon-Broome criteria for FH (1 from Ambry Genetics and 2 from Cardiovascular Research Group,Instituto Nacional de Saude Doutor Ricardo Jorge) ---- PP4 is Met
PP3
REVEL = 0.708. It is not above 0.75, splicing evaluation is required. Functional data on splicing not available. A) variant located -3 to +6 from canonical donor site MES scores: canonical site variant = 5.84; canonical site wt = 7.67. Ratio variant/wt canonical: 5.84/7.67 = 0.761. --- ratio is below 0.8, so PP3 is Met
PM1
Missense at codon 231. PM2 is Met and Cys231 is one of the 60 Cys residues listed, so PM1 is Met
PM2
No population data was found for this variant in gnomAD (gnomAD v2.1.1).
Not Met criteria codes
BA1
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
PVS1
Missense variant, PVS1 Not Met
BS4
no non-segregations were identified, so BS4 is Not Met
BS3
no functional assays performed, not applicable
BS1
No population data was found for this variant in gnomAD (gnomAD v2.1.1).
BP2
not identified in individuals with other variants, so BP2 is Not Met
BP3
Not applicable
BP4
REVEL = 0.708. It is not below 0.15, so BP4 is Not Met
BP1
Not applicable
BP5
Not applicable
BP7
Missense variant, so BP7 is not applicable
PS2
no de novo cases were identified, so PS2 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
PP1
variant segregates with phenotype in 1 informative meiosis in 1 family from Cardiovascular Research Group,Instituto Nacional de Saude Doutor Ricardo Jorge: 1 affected family member has the variant. not enough evidence to meet PP1 --- PP1 is Not Met
PP2
Not applicable
PM3
not identified in individuals with other variants, so PM3 is Not Met
PM4
Missense variant, not applicable
PM5
Variant meets PM1, so PM5 is not applicable.
PM6
no de novo cases were identified, so PM6 is Not Met
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