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>A (p.Gly461Ser)

CA023472

36456 (ClinVar)

Gene: LDLR
Condition: hypercholesterolemia, familial
Inheritance Mode: Semidominant inheritance
Link to MONDO
UUID: 9f30cee9-8799-4851-be7e-f9dd458f72e9
Approved on: 2024-02-23
Published on: 2025-02-24

HGVS expressions

NM_000527.5:c.1381G>A
NM_000527.5(LDLR):c.1381G>A (p.Gly461Ser)
NC_000019.10:g.11113557G>A
CM000681.2:g.11113557G>A
NC_000019.9:g.11224233G>A
CM000681.1:g.11224233G>A
NC_000019.8:g.11085233G>A
NG_009060.1:g.29177G>A
ENST00000252444.10:c.1639G>A
ENST00000559340.2:c.1381G>A
ENST00000560467.2:c.1261G>A
ENST00000558518.6:c.1381G>A
ENST00000252444.9:c.1635G>A
ENST00000455727.6:c.877G>A
ENST00000535915.5:c.1258G>A
ENST00000545707.5:c.1000G>A
ENST00000557933.5:c.1381G>A
ENST00000558013.5:c.1381G>A
ENST00000558518.5:c.1381G>A
ENST00000559340.1:c.102G>A
ENST00000560467.1:c.861G>A
NM_000527.4:c.1381G>A
NM_001195798.1:c.1381G>A
NM_001195799.1:c.1258G>A
NM_001195800.1:c.877G>A
NM_001195803.1:c.1000G>A
NM_001195798.2:c.1381G>A
NM_001195799.2:c.1258G>A
NM_001195800.2:c.877G>A
NM_001195803.2:c.1000G>A
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Uncertain Significance

Met criteria codes 3
PP4 PM2 BP4
Not Met criteria codes 19
PS2 PS4 PS3 PS1 PP1 PP3 PM6 PM3 PM1 PM4 PM5 PVS1 BA1 BS2 BS4 BS3 BS1 BP7 BP2

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>A (p.Gly461Ser) variant is classified as Uncertain significance - insufficient evidence for Familial Hypercholesterolemia by applying ACMG/AMP evidence codes PM2, BP4 and PP4 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 = 0.0001732 in Admixed American exomes (gnomAD v4.0.0); this is less than 0.0002. BP4: No REVEL score, functional data on splicing is not available. MES: A) not on limits. B) not on limit creating AG; on limit however does not create GT. C) there is a GT nearby: Var cryptic donor/Wt cryptic donor= -12.59/ -14.70= 0.86 ; Var cryptic donor/Wt donor= -12.59/5.46= -2.3, alternative splicing not predicted and REVEL is <0.5, therefore BP4 is met. PP4: One case reported in PMID 36229376 (Tada et al., 2022) fulfilling Japan Atherosclerosis Society criteria for FH.
Met criteria codes
PP4
One case reported in PMID 36229376 (ST2) fulfil Japan Atherosclerosis Society criteria.
PM2
MAF = 0.0001732 in Admixed American exomes gnomAD version 4.0.0, this is less than .0002.
BP4
No REVEL score, functional data on splicing is not available. MES: A) not on limits. B) not on limit creating AG; on limit however does not create GT. C) there is a GT nearby: Var cryptic donor/Wt cryptic donor= -12.59/ -14.70= 0.86 ; Var cryptic donor/Wt donor= -12.59/5.46= -2.3, alternative splicing not predicted and REVEL is <0.5, therefore BP4 is met.
Not Met criteria codes
PS2
Not met.
PS4
Not met.
PS3
No data available.
PS1
Not met.
PP1
Not met.
PP3
No REVEL, splicing evaluation required. MES: A) not on limits. B) not on limit creating AG; on limit however does not create GT. C) there is a GT nearby: Var cryptic donor/Wt cryptic donor= -12.59/ -14.70= 0.86 ; Var cryptic donor/Wt donor= -12.59/5.46= -2.3, alternative splicing not predicted and REVEL is <0.5, therefore BP4 is met.
PM6
Not met.
PM3
Not met.
PM1
Not located in exon 4 or at a cysteine residue.
PM4
Not an in-frame deletion/insertion.
PM5
Not met.
PVS1
Not a null variant.
BA1
Not met.
BS2
Not met.
BS4
Not met.
BS3
No data available.
BS1
Not met.
BP7
Not a synonymous variant.
BP2
Not met.
Curation History
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