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]
Link to SEPIO compliant JSON-LD document
  • Gene obtained from curated document aligns with the Allele Registry but not with ClinVar data
  • No CSPEC related information was provided by the message!
  • No CSPEC computed assertion could be determined for this classification!
  • See Evidence submitted by expert panel for details.

Variant: NM_000527.5(LDLR):c.811G>A (p.Val271Ile)

CA023769

189297 (ClinVar)

Gene: LDLR
Condition: hypercholesterolemia, familial
Inheritance Mode: Semidominant inheritance
Link to MONDO
UUID: 8b200ce4-e051-4069-bed7-419e0ce94047
Approved on: 2023-06-23
Published on: 2024-09-25

HGVS expressions

NM_000527.5:c.811G>A
NM_000527.5(LDLR):c.811G>A (p.Val271Ile)
NC_000019.10:g.11106681G>A
CM000681.2:g.11106681G>A
NC_000019.9:g.11217357G>A
CM000681.1:g.11217357G>A
NC_000019.8:g.11078357G>A
NG_009060.1:g.22301G>A
ENST00000252444.10:c.1069G>A
ENST00000559340.2:c.811G>A
ENST00000560467.2:c.811G>A
ENST00000558518.6:c.811G>A
ENST00000252444.9:c.1065G>A
ENST00000455727.6:c.314-711G>A
ENST00000535915.5:c.688G>A
ENST00000545707.5:c.430G>A
ENST00000557933.5:c.811G>A
ENST00000558013.5:c.811G>A
ENST00000558518.5:c.811G>A
ENST00000558528.1:n.326G>A
ENST00000560467.1:c.411G>A
NM_000527.4:c.811G>A
NM_001195798.1:c.811G>A
NM_001195799.1:c.688G>A
NM_001195800.1:c.314-711G>A
NM_001195803.1:c.430G>A
NM_001195798.2:c.811G>A
NM_001195799.2:c.688G>A
NM_001195800.2:c.314-711G>A
NM_001195803.2:c.430G>A

Uncertain Significance

Met criteria codes 4
BP4 PP1 PP4 PM2
Not Met criteria codes 17
BA1 BP2 BP3 BS2 BS3 BS1 PP3 PVS1 PM6 PM3 PM1 PM4 PM5 PS2 PS4 PS3 PS1

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.811G>A (p.Val271Ile) variant is classified as Uncertain significance - insufficient evidence for Familial Hypercholesterolemia by applying ACMG/AMP evidence codes PM2, PP1, PP4, and BP4 as defined by the ClinGen Familial Hypercholesterolemia Expert Panel LDLR-specific variant curation guidelines (specification version 1.2) on 23 June 2023. The supporting evidence is as follows: PM2: PopMax MAF = 0.00011 (0.011%) in East Asian exomes+genomes (gnomAD v2.1.1). BP4: REVEL=0.33. It is below 0.5, splicing evaluation required. Functional data on splicing not available. A) not on limits. B) does not create GT. C) there is no GT nearby. Variant is not predicted to alter splicing. PP1: Variant segregates with FH phenotype in 3 informative meioses in 1 family from PMID 26036859 (Brænne I et al., 2016). 2 affected family members have the variant. PP4: Variant meets PM2 and is identified in 1 index case with DLCN score >=6 from PMID 26036859 (Brænne I et al., 2016: LDL-C 286 mg/dl and a history of premature CAD, DLCN=7).
Met criteria codes
BP4
REVEL=0.33. It is below 0.5, splicing evaluation required. Functional data on splicing not available. A) not on limits. B) does not create GT C) there is no GT nearby Variant is not predicted to alter splicing. So, BP4 is met.
PP1
Variant segregates with FH phenotype in 3 informative meioses in 1 families from PMID 26036859. 2 affected family members have the variant. So, PP1 is met.
PP4
Variant meets PM2. PMID 26036859 (Brænne I et al) 2016, 1 patient who fulfill DLCN criteria of probable FH (LDL-C= = 286 mg/dl and a history of premature CAD, DLCN=7). So, PP4 is met.
PM2
PopMax MAF = 0.00011 (0.011%) in East Asian exomes+genomes (gnomAD v2.1.1). So PM2 is met.
Not Met criteria codes
BA1
PopMax MAF = 0.00011 (0.011%) in East Asian exomes+genomes (gnomAD v2.1.1).
BP2
No data available.
BP3
No in-frame deletions/insertions
BS2
No data available.
BS3
No functional study available.
BS1
PopMax MAF = 0.00011 (0.011%) in East Asian exomes+genomes (gnomAD v2.1.1).
PP3
REVEL=0.33. It is below 0.75, splicing evaluation required. Functional data on splicing not available. A) not on limits. B) does not create GT C) there is no GT nearby Variant is not predicted to alter splicing.
PVS1
Not a null variant
PM6
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
PM3
No data available.
PM1
Not in exon 4. Not a cysteine residue.
PM4
No in-frame deletions/insertions
PM5
No other missense variant in the same codon.
PS2
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
PS4
Variant meets PM2 and is identified in 1 case from PMID 26036859.
PS3
No functional study available.
PS1
No other missense variant in the same codon.
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