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 label mismatch: LDLR vs undefined
  • 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.1761C>G (p.Ser587Arg)

CA036457

252021 (ClinVar)

Gene: LDLR
Condition: hypercholesterolemia, familial
Inheritance Mode: Semidominant inheritance
Link to MONDO
UUID: 2f2fa622-b260-4dae-8332-c06d4eb16d25
Approved on: 2025-03-28
Published on: 2025-06-04

HGVS expressions

NM_000527.5:c.1761C>G
NM_000527.5(LDLR):c.1761C>G (p.Ser587Arg)
NC_000019.10:g.11116914C>G
CM000681.2:g.11116914C>G
NC_000019.9:g.11227590C>G
CM000681.1:g.11227590C>G
NC_000019.8:g.11088590C>G
NG_009060.1:g.32534C>G
ENST00000252444.10:c.2019C>G
ENST00000559340.2:c.1705+702C>G
ENST00000560467.2:c.1641C>G
ENST00000558518.6:c.1761C>G
ENST00000252444.9:c.2015C>G
ENST00000455727.6:c.1257C>G
ENST00000535915.5:c.1638C>G
ENST00000545707.5:c.1380C>G
ENST00000557933.5:c.1761C>G
ENST00000558013.5:c.1761C>G
ENST00000558518.5:c.1761C>G
ENST00000559340.1:c.426+702C>G
NM_000527.4:c.1761C>G
NM_001195798.1:c.1761C>G
NM_001195799.1:c.1638C>G
NM_001195800.1:c.1257C>G
NM_001195803.1:c.1380C>G
NM_001195798.2:c.1761C>G
NM_001195799.2:c.1638C>G
NM_001195800.2:c.1257C>G
NM_001195803.2:c.1380C>G
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Uncertain Significance

Met criteria codes 1
PM2
Not Met criteria codes 11
PS4 PS3 BA1 PP1 PP4 PP3 BS2 BS4 BS3 BS1 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

PDF
Criteria Specification Approval History
Criteria Specifications for this VCEP
Evidence submitted by expert panel
Familial Hypercholesterolemia VCEP
The NM_000527.5(LDLR):c.1761C>G (p.Ser587Arg) variant is classified as Uncertain significance - insufficient evidence for Familial Hypercholesterolemia by applying ACMG/AMP evidence code PM2 as defined by the ClinGen Familial Hypercholesterolemia Expert Panel LDLR-specific variant curation guidelines (specification version 1.2) on 28 March 2025. The supporting evidence is as follows: PM2: PopMax MAF = 0.00001356 (0.0014%) in European (non-Finnish) (gnomAD v4.1.0).
Met criteria codes
PM2
PopMax MAF = 0.00001356 (0.0014%) in European (non-Finnish) (gnomAD v4.0). PM2 is met since PopMax MAF<0.02%.
Not Met criteria codes
PS4
not met, (no information of index cases or report of segregation data/cases)
PS3
not met (no information or reports of functional data).
BA1
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
PP1
not met, (no information of index cases or report of segregation data/cases)
PP4
not met, (no information of index cases or report of segregation data/cases)
PP3
REVEL = 0.746. REVEL not above 0.75 and not below 0.50. Splicing evaluation is required. Functional data on splicing not available. A) not on limits, B) variant does not creates GT or AG, C) There is an AG nearby (and there is no GT nearby). MES scores: variant cryptic score (TCAAGGATC) = -23.44, wt cryptic (TCAAGCATC) = -32.62, canonical acceptor = 7.93. Ratio variant cryptic/wt cryptic: -23.44/-32.62 = 0.72 --- it is not above 1.1, and Ratio variant cryptic/canonical acceptor: -23.44/7.93= -12.6 --- it is not above 0.9. Therefore, PP3 is not met.
BS2
not met, (no information of index cases or report of segregation data/cases)
BS4
not met, (no information of index cases or report of segregation data/cases)
BS3
not met (no information or reports of functional data).
BS1
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
BP4
REVEL = 0.746. REVEL not above 0.75 and not below 0.50. Splicing evaluation is required. Functional data on splicing not available. A) not on limits, B) variant does not creates GT or AG, C) There is an AG nearby (and there is no GT nearby). MES scores: variant cryptic score (TCAAGGATC) = -23.44, wt cryptic (TCAAGCATC) = -32.62, canonical acceptor = 7.93. Ratio variant cryptic/wt cryptic: -23.44/-32.62 = 0.72 --- it is not above 1.1, and Ratio variant cryptic/canonical acceptor: -23.44/7.93= -12.6 --- it is not above 0.9. Therefore, PP3 is not met.
Curation History
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