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]
  • Gene obtained from curated document aligns with the Allele Registry but not with ClinVar data
  • No CSPEC computed assertion could be determined for this classification!

Variant: NM_000527.5(LDLR):c.1285G>T (p.Val429Leu)

CA10585386

251767 (ClinVar)

Gene: LDLR
Condition: hypercholesterolemia, familial
Inheritance Mode: Semidominant inheritance
Link to MONDO
UUID: ff1c9255-fa91-41ab-9f63-06538fa20fc3
Approved on: 2023-03-27
Published on: 2024-10-04

HGVS expressions

NM_000527.5:c.1285G>T
NM_000527.5(LDLR):c.1285G>T (p.Val429Leu)
NC_000019.10:g.11113376G>T
CM000681.2:g.11113376G>T
NC_000019.9:g.11224052G>T
CM000681.1:g.11224052G>T
NC_000019.8:g.11085052G>T
NG_009060.1:g.28996G>T
ENST00000252444.10:c.1543G>T
ENST00000559340.2:c.1285G>T
ENST00000560467.2:c.1165G>T
ENST00000558518.6:c.1285G>T
ENST00000252444.9:c.1539G>T
ENST00000455727.6:c.781G>T
ENST00000535915.5:c.1162G>T
ENST00000545707.5:c.904G>T
ENST00000557933.5:c.1285G>T
ENST00000558013.5:c.1285G>T
ENST00000558518.5:c.1285G>T
ENST00000559340.1:c.6G>T
ENST00000560173.1:n.284G>T
ENST00000560467.1:c.765G>T
NM_000527.4:c.1285G>T
NM_001195798.1:c.1285G>T
NM_001195799.1:c.1162G>T
NM_001195800.1:c.781G>T
NM_001195803.1:c.904G>T
NM_001195798.2:c.1285G>T
NM_001195799.2:c.1162G>T
NM_001195800.2:c.781G>T
NM_001195803.2:c.904G>T
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Pathogenic

Met criteria codes 5
PP4 PP3 PM5 PM2 PS1
Not Met criteria codes 21
PP1 PP2 PM3 PM1 PM4 PM6 PVS1 BA1 BS2 BS3 BS4 BS1 BP2 BP3 BP4 BP1 BP5 BP7 PS3 PS2 PS4

Evidence Links 0

Expert Panel

Criteria Specification Information

Criteria Specification: ClinGen Familial Hypercholesterolemia Expert Panel Specifications to the ACMG/AMP Variant Classification Guidelines Version 1.2

PDF
Criteria Specification Approval History
Criteria Specifications for this VCEP
Evidence submitted by expert panel
Familial Hypercholesterolemia VCEP
The NM_000527.5(LDLR):c.1285G>T (p.Val429Leu) variant is classified as Pathogenic for Familial Hypercholesterolemia by applying ACMG/AMP evidence codes PS1, PM2, PM5, PP3 and PP4 as defined by the ClinGen Familial Hypercholesterolemia Expert Panel LDLR-specific variant curation guidelines (specification version 1.2) on 27 March 2023. The supporting evidence is as follows: PM2: This variant is absent from gnomAD (gnomAD v2.1.1). PP3: REVEL = 0.764. PM5: There is 1 missense variant in the same codon classified as Pathogenic by these guidelines, NM_000527.5(LDLR): c.1285G<A (p.Val429Met), ClinVar ID 3694. PS1: There is 1 missense variant in the same codon predicting the same amino acid change classified as Pathogenic by these guidelines, NM_000527.5(LDLR): c.1285G>C (p.Val429Leu), ClinVar ID 226353. PP4: Variant meets PM2 and is identified in at least 1 index case meeting Simon Broome criteria for FH from PMID 9727746 (Nissen et al., 1998).
Met criteria codes
PP4
Variant meets PM2 and is identified in at least 1 index case with SB criteria of FH (cholesterol levels above the 95th percentile for age and sex and associated with either a family history of either hypercholesterolemia, premature development of atherosclerosis, or tendon xanthomas) from PMID 9727746.
PP3
REVEL = 0.764. It is above 0.75.
PM5
PM5: NM_000527.5(LDLR): c.1285G<A p.Val429Met (ClinVar ID: 3694) - Pathogenic by these guidelines There is 1 variant in the same codon classified as Pathogenic by these guidelines.
PM2
This variant is absent from gnomAD (gnomAD v2.1.1).
PS1
NM_000527.5(LDLR): c.1285G>C p.Val429Leu (ClinVar ID: 226353) - Pathogenic by these guidelines. Missense variant at the same codon as a variant classified pathogenic, and predicts the same amino acid change.
Not Met criteria codes
PP1
no family members tested
PP2
not applicable
PM3
not identified in index cases with more than 1 variant
PM1
variant is missense and meets PM2, but is not in exon 4 and does not alter Cys
PM4
missense - not applicable
PM6
no de novo occurrence
PVS1
missense and not in exon 1 - not applicable
BA1
This variant is absent from gnomAD (gnomAD v2.1.1).
BS2
not identified in normolipidemic individuals
BS3
no published functional studies
BS4
no family members tested
BS1
This variant is absent from gnomAD (gnomAD v2.1.1).
BP2
not identified in index cases with more than 1 variant
BP3
not applicable
BP4
REVEL = 0.764. It is not below 0.50.
BP1
not applicable
BP5
not applicable
BP7
missense - not applicable
PS3
no published functional studies
PS2
no de novo occurrence
PS4
Variant meets PM2 and is identified in at least 1 index case with SB criteria of FH (cholesterol levels above the 95th percentile for age and sex and associated with either a family history of either hypercholesterolemia, premature development of atherosclerosis, or tendon xanthomas) from PMID 9727746. not enough for PS4_supporting
Curation History
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