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

Variant: NM_000527.5(LDLR):c.1381G>T (p.Gly461Cys)

CA023475

183113 (ClinVar)

Gene: LDLR
Condition: hypercholesterolemia, familial
Inheritance Mode: Semidominant inheritance
Link to MONDO
UUID: 06d695fb-5e52-4733-8541-911f729d96cf
Approved on: 2024-02-23
Published on: 2025-02-24

HGVS expressions

NM_000527.5:c.1381G>T
NM_000527.5(LDLR):c.1381G>T (p.Gly461Cys)
NC_000019.10:g.11113557G>T
CM000681.2:g.11113557G>T
NC_000019.9:g.11224233G>T
CM000681.1:g.11224233G>T
NC_000019.8:g.11085233G>T
NG_009060.1:g.29177G>T
ENST00000252444.10:c.1639G>T
ENST00000559340.2:c.1381G>T
ENST00000560467.2:c.1261G>T
ENST00000558518.6:c.1381G>T
ENST00000252444.9:c.1635G>T
ENST00000455727.6:c.877G>T
ENST00000535915.5:c.1258G>T
ENST00000545707.5:c.1000G>T
ENST00000557933.5:c.1381G>T
ENST00000558013.5:c.1381G>T
ENST00000558518.5:c.1381G>T
ENST00000559340.1:c.102G>T
ENST00000560467.1:c.861G>T
NM_000527.4:c.1381G>T
NM_001195798.1:c.1381G>T
NM_001195799.1:c.1258G>T
NM_001195800.1:c.877G>T
NM_001195803.1:c.1000G>T
NM_001195798.2:c.1381G>T
NM_001195799.2:c.1258G>T
NM_001195800.2:c.877G>T
NM_001195803.2:c.1000G>T
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Likely Pathogenic

Met criteria codes 4
PP4 PM2 PP1_Strong PS4_Supporting
Not Met criteria codes 17
PS2 PS3 PS1 PVS1 PP3 BA1 PM3 PM4 PM5 PM6 BS2 BS4 BS3 BS1 BP7 BP2 BP4

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

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Criteria Specification Approval History
Criteria Specifications for this VCEP
Evidence submitted by expert panel
Familial Hypercholesterolemia VCEP
The NM_000527.5(LDLR):c.1381G>T (p.Gly461Cys) variant is classified as Likely Pathogenic for Familial Hypercholesterolemia by applying ACMG/AMP evidence codes PP1_Strong, PM2, PP4 and PS4_Supporting as defined by the ClinGen Familial Hypercholesterolemia Expert Panel LDLR-specific variant curation guidelines (specification version 1.2) on 23 February 2024. The supporting evidence is as follows: PM2: MAF= 0.00002331 (0.002331%) in European (Non-Finnish) exomes (gnomAD v4.0.0). PS4_Supporting, PP4: Three unrelated index cases fulfill FH criteria, reported in PMID 23815734 (Mollaki et al., 2013 - Greece) and 16465405 (Cefalù et al., 2006 - Italy). PP1_Strong: Variant segregates with phenotype in 8 informative meiosis from 3 families, affected relatives tested positive for the variant, reported in PMID 23815734 and 16465405.
Met criteria codes
PP4
Three unrelated index cases fulfill FH criteria, reported in PMID 23815734 and 16465405.
PM2
MAF= 0.00002331 (.002331 %) in European (Non-Finnish) exomes gnomAD version 4.0.0
PP1_Strong
Variant segregates with phenotype in eight informative meiosis from three families, affected relatives tested positive for the variant, reported in PMID 23815734 and 16465405.
PS4_Supporting
Three unrelated index cases fulfill FH criteria, reported in PMID 23815734 and 16465405.
Not Met criteria codes
PS2
Not met.
PS3
Not met.
PS1
Not met.
PVS1
Not a null variant.
PP3
REVEL= 0.574, it is not above 0.75, splicing evaluation required. Scenario A) Not in limits Scenario B) Does not create AG Scenario C) Not in limits. Variant is not predicted to alter splicing.
BA1
Not met.
PM3
Not met.
PM4
Not an in-frame deletion/insertion.
PM5
Not met.
PM6
Not met.
BS2
Not met.
BS4
Not met.
BS3
PMID 25647241 did not study whole LDLR cycle.
BS1
Not met.
BP7
Not a synonymous variant.
BP2
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
BP4
REVEL= 0.574, it is not below 0.50.
Curation History
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