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.564C>T (p.Tyr188=)

CA043947

226327 (ClinVar)

Gene: LDLR
Condition: hypercholesterolemia, familial
Inheritance Mode: Semidominant inheritance
Link to MONDO
UUID: 149df43d-e31a-4e96-949d-58c5f01d5516
Approved on: 2024-08-30
Published on: 2024-10-03

HGVS expressions

NM_000527.5:c.564C>T
NM_000527.5(LDLR):c.564C>T (p.Tyr188=)
NC_000019.10:g.11105470C>T
CM000681.2:g.11105470C>T
NC_000019.9:g.11216146C>T
CM000681.1:g.11216146C>T
NC_000019.8:g.11077146C>T
NG_009060.1:g.21090C>T
ENST00000252444.10:c.822C>T
ENST00000559340.2:c.564C>T
ENST00000560467.2:c.564C>T
ENST00000558518.6:c.564C>T
ENST00000252444.9:c.818C>T
ENST00000455727.6:c.314-1922C>T
ENST00000535915.5:c.441C>T
ENST00000545707.5:c.314-1095C>T
ENST00000557933.5:c.564C>T
ENST00000558013.5:c.564C>T
ENST00000558518.5:c.564C>T
ENST00000560467.1:c.164C>T
NM_000527.4:c.564C>T
NM_001195798.1:c.564C>T
NM_001195799.1:c.441C>T
NM_001195800.1:c.314-1922C>T
NM_001195803.1:c.314-1095C>T
NM_001195798.2:c.564C>T
NM_001195799.2:c.441C>T
NM_001195800.2:c.314-1922C>T
NM_001195803.2:c.314-1095C>T
More

Likely Benign

Met criteria codes 2
BP4 BP7
Not Met criteria codes 22
PS4 PS3 PS1 PP1 PP4 PP3 PP2 PM2 PM3 PM1 PM4 PM5 PVS1 BA1 BS2 BS4 BS3 BS1 BP2 BP3 BP1 BP5

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.564C>T p.(Tyr188=) variant is classified as Likely benign for Familial Hypercholesterolemia by applying ACMG/AMP evidence codes BP4 and BP7 as defined by the ClinGen Familial Hypercholesterolemia Expert Panel LDLR-specific variant curation guidelines (specification version 1.2) on 30 August 2024. The supporting evidence is as follows: BP4: No REVEL, splicing evaluation needed. Functional data on splicing not available. A) Variant not on limits B) variant is exonic and at least 50 bp downstream from the canonical acceptor site, but it does not create GT. Variant is not predicted to alter splicing. BP7: Variant meets BP4 and is synonymous.
Met criteria codes
BP4
No REVEL, splicing evaluation needed. Functional data on splicing not available. A) Variant not on limits B) variant is exonic and at least 50 bp downstream from the canonical acceptor site, but it does not create GT. Variant is not predicted to alter splicing, so BP4 is met
BP7
Variant meets BP4 and is synonymous.
Not Met criteria codes
PS4
Identified in 1 index cases fulfilling validated clinical criteria for FH, after alternative causes of high cholesterol were excluded (1 case with DLCN criteria ≥6 from Cardiovascular Genetics Laboratory (PathWest Laboratory Medicine – Fiona Stanley Hospital), West Australia. But variant does not meet PM2, so not met
PS3
no published functional studies
PS1
variant is synonymous, so not applicable
PP1
Variant segregates with phenotype in 1 informative meioses in 1 family from Cardiovascular Genetics Laboratory (PathWest Laboratory Medicine – Fiona Stanley Hospital), West Australia: 1 non-carrier family member with LDL-C <50th percentil. PP1 requires at least 2 informative meiosis, so not met
PP4
Identified in 1 index cases fulfilling validated clinical criteria for FH, after alternative causes of high cholesterol were excluded (1 case with DLCN criteria ≥6 from Cardiovascular Genetics Laboratory (PathWest Laboratory Medicine – Fiona Stanley Hospital), West Australia. But variant does not meet PM2, so not met
PP3
No REVEL, splicing evaluation needed. Functional data on splicing not available. A) Variant not on limits B) variant is exonic and at least 50 bp downstream from the canonical acceptor site, but it does not create GT. Variant is not predicted to alter splicing, so not met.
PP2
not applicable
PM2
PopMax MAF = 0.0003008 (0.03%) in European (non-Finnish) exomes+genomes (gnomAD v4.1.0). It is not below 0.02%, so not met
PM3
variant not identified in index cases with more than 1 variant
PM1
variant is synonymous, so not applicable
PM4
variant is synonymous, so not applicable
PM5
variant is synonymous, so not applicable
PVS1
variant is synonymous, so not applicable
BA1
FAF = 0.0002747 (0.02747%) in European non-Finnish exomes+genomes (gnomAD v4.1.0). It is not above 0.5%, so not met
BS2
Variant identified in 2 heterozygous unaffected family members with variant from Cardiovascular Genetics Laboratory (PathWest Laboratory Medicine WA). Not enough, so not met
BS4
Variant does not segregate with FH phenotype in at least 2 informative meiosis from 1 family from Cardiovascular Genetics Laboratory (PathWest Laboratory Medicine WA): 2 family members carrying the variant with LDL-C <50th percentile. BS4 requires lack of segregation in ≥2 index case unrelated families, so BS4 is not met
BS3
no published functional studies
BS1
FAF = 0.0002747 (0.02747%) in European non-Finnish exomes+genomes (gnomAD v4.1.0). It is not above 0.2%, so not met
BP2
variant not identified in index cases with more than 1 variant
BP3
not applicable
BP1
not aplicable
BP5
not applicable
Curation History
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