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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Variant: NM_000527.5(LDLR):c.1223A>T (p.Glu408Val)

CA10585364

251740 (ClinVar)

Gene: LDLR
Condition: hypercholesterolemia, familial
Inheritance Mode: Semidominant inheritance
Link to MONDO
UUID: 7b85f1a3-4093-43b4-9136-ec4a602c987b

HGVS expressions

NM_000527.5:c.1223A>T
NM_000527.5(LDLR):c.1223A>T (p.Glu408Val)
NC_000019.10:g.11113314A>T
CM000681.2:g.11113314A>T
NC_000019.9:g.11223990A>T
CM000681.1:g.11223990A>T
NC_000019.8:g.11084990A>T
NG_009060.1:g.28934A>T
ENST00000558518.6:c.1223A>T
ENST00000252444.9:n.1477A>T
ENST00000455727.6:c.719A>T
ENST00000535915.5:c.1100A>T
ENST00000545707.5:c.842A>T
ENST00000557933.5:c.1223A>T
ENST00000558013.5:c.1223A>T
ENST00000558518.5:c.1223A>T
ENST00000560173.1:n.222A>T
ENST00000560467.1:n.703A>T
NM_000527.4:c.1223A>T
NM_001195798.1:c.1223A>T
NM_001195799.1:c.1100A>T
NM_001195800.1:c.719A>T
NM_001195803.1:c.842A>T
NM_001195798.2:c.1223A>T
NM_001195799.2:c.1100A>T
NM_001195800.2:c.719A>T
NM_001195803.2:c.842A>T

Likely Pathogenic

Met criteria codes 5
PP1_Moderate PP4 PP3 PM2 PS4_Moderate
Not Met criteria codes 21
BA1 PVS1 BS4 BS3 BS1 BS2 BP5 BP7 BP2 BP3 BP4 BP1 PS2 PS3 PS1 PP2 PM3 PM1 PM4 PM5 PM6

Evidence Links 0

Expert Panel

Criteria Specification Information

Criteria Specification: ClinGen Familial Hypercholesterolemia Expert Panel Specifications to the ACMG/AMP Variant Classification Guidelines Version 1.1

PDF
Criteria Specification Approval History
Criteria Specifications for this VCEP
Evidence submitted by expert panel
Familial Hypercholesterolemia VCEP
The NM_000527.5(LDLR):c.1223A>T (p.Glu408Val) variant is classified as Likely pathogenic for Familial Hypercholesterolemia by applying evidence codes PP1_Moderate, PM2, PS4_Moderate, 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: PP1_moderate - variant segregates with FH phenotype in 5 informative meiosis (data from 3 families: F1 - 2 affected family members have the variant, F2 - 2 affected family members have the variant, F3 - 1 affected family member has the variant) from the Molecular Genetics Laboratory (Centre for Cardiovascular Surgery and Transplantation), so PP1_Moderate is met. PM2 - This variant was not identified in gnomAD (gnomAD v2.1.1), so PM2 is met. PS4_moderate - variant meets PM2 and was identified in 6 unrelated index cases, all fulfilling Simon-Broome criteria of definite FH, from the Molecular Genetics Laboratory (Centre for Cardiovascular Surgery and Transplantation), so PS4_Moderate is met. PP3 - REVEL = 0.908. It is above 0.75, so PP3 is met. PP4 - variant meets PM2 and was identified in 6 unrelated index cases (see details in PS4), so PP4 is met.
Met criteria codes
PP1_Moderate
variant segregates with FH phenotype in 5 informative meiosis (data from 3 families: F1 - 2 affected family members have the variant, F2 - 2 affected family members have the variant, F3 - 1 affected family member has the variant) from the Molecular Genetics Laboratory (Centre for Cardiovascular Surgery and Transplantation), so PP1_Moderate is met
PP4
variant meets PM2 and was identified in 6 unrelated index cases, all fulfilling Simon-Broome criteria of definite FH, from the Molecular Genetics Laboratory (Centre for Cardiovascular Surgery and Transplantation), so PP4 is met.
PP3
REVEL = 0.908. It is above 0.75, so PP3 is met
PM2
This variant was not identified in gnomAD (gnomAD v2.1.1), so PM2 is met
PS4_Moderate
variant meets PM2 and was identified in 6 unrelated index cases, all fulfilling Simon-Broome criteria of definite FH, from the Molecular Genetics Laboratory (Centre for Cardiovascular Surgery and Transplantation), so PS4_Moderate is met.
Not Met criteria codes
BA1
This variant was not identified in gnomAD (gnomAD v2.1.1), so not met
PVS1
variant is missense and not in initiation codon, so not met
BS4
no lack of segregation was identified, so not met
BS3
no functional study performed, so not met
BS1
This variant was not identified in gnomAD (gnomAD v2.1.1), so not met
BS2
not identified in normolipidemic individuals: 0/100 normolipidemic individuals from Molecular Genetics Laboratory (Centre for Cardiovascular Surgery and Transplantation), so not met
BP5
not applicable
BP7
variant is missense, so not met
BP2
no other variants identified in index cases, so not met
BP3
not applicable
BP4
REVEL = 0.908. It is not below 0.50, so BP4 is not met
BP1
not applicable
PS2
no de novo occurrence
PS3
no functional study performed, so not met
PS1
no other missense variant leads to the same amino acid change in the same codon, so not met
PP2
not applicable
PM3
no other variants identified in index cases, so not met
PM1
variant is not in exon 4 and does not alter Cys, so not met
PM4
variant is missense, so not met
PM5
4 other missense variants is the same codon: - NM_000527.5(LDLR):c.1222G>C (p.Glu408Gln) - VUS by these guidelines - NM_000527.5(LDLR):c.1222G>A (p.Glu408Lys) - classified as Likely pathogenic by the FH VCEP, with these guidelines - NM_000527.5(LDLR):c.1223A>C (p.Glu408Ala) - VUS by these guidelines - NM_000527.5(LDLR):c.1224G>C (p.Glu408Asp) - VUS by these guidelines no variant is classified as Pathogenic by these guidelines, so not met.
PM6
no de novo occurrence
Approved on: 2021-12-16
Published on: 2022-07-11
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