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.1837G>A (p.Val613Ile)

CA023595

161288 (ClinVar)

Gene: LDLR
Condition: hypercholesterolemia, familial
Inheritance Mode: Semidominant inheritance
Link to MONDO
UUID: 9ea4b7fb-e7b9-43aa-b887-aaedf6ae8270
Approved on: 2025-03-28
Published on: 2025-06-30

HGVS expressions

NM_000527.5:c.1837G>A
NM_000527.5(LDLR):c.1837G>A (p.Val613Ile)
NC_000019.10:g.11116990G>A
CM000681.2:g.11116990G>A
NC_000019.9:g.11227666G>A
CM000681.1:g.11227666G>A
NC_000019.8:g.11088666G>A
NG_009060.1:g.32610G>A
ENST00000252444.10:c.2095G>A
ENST00000559340.2:c.1705+778G>A
ENST00000560467.2:c.1717G>A
ENST00000558518.6:c.1837G>A
ENST00000252444.9:c.2091G>A
ENST00000455727.6:c.1333G>A
ENST00000535915.5:c.1714G>A
ENST00000545707.5:c.1456G>A
ENST00000557933.5:c.1837G>A
ENST00000558013.5:c.1837G>A
ENST00000558518.5:c.1837G>A
ENST00000559340.1:c.426+778G>A
NM_000527.4:c.1837G>A
NM_001195798.1:c.1837G>A
NM_001195799.1:c.1714G>A
NM_001195800.1:c.1333G>A
NM_001195803.1:c.1456G>A
NM_001195798.2:c.1837G>A
NM_001195799.2:c.1714G>A
NM_001195800.2:c.1333G>A
NM_001195803.2:c.1456G>A
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Uncertain Significance

Met criteria codes 3
PM2 PS4_Supporting PP4
Not Met criteria codes 18
PM3 PM1 PM4 PM5 PM6 BA1 BS4 BS3 BS1 BS2 BP2 BP3 BP4 PS2 PS3 PS1 PP1 PP3

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.1837G>A (p.Val613Ile) variant is classified as Uncertain significance - insufficient evidence for Familial Hypercholesterolemia by applying ACMG/AMP evidence codes PM2, PS4_Supporting and PP4 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 = 0.00005340 (0.005%) in African/African American exomes+genomes (gnomAD v4.1.0). PS4_Supporting, PP4: Variant meets PM2 and is identified in 2 unrelated index cases meeting FH criteria (1 case in PMID 19837725 (Whittall et al., 2010), UK; 1 case in PMID 16250003 (Fouchier et al., 2005), Netherlands).
Met criteria codes
PM2
PopMax MAF = 0.00005340 (0.005%) in African/African American exomes+genomes (gnomAD v4.1.0). So, PM2 is met.
PS4_Supporting
Variant meets PM2 and is identified in 2 index cases (1 case with Simon Broome criteria of possible/definite FH in PMID 19837725 (Whittall et al., 2010); 1 case with FH based on Defesche in PMID: 16250003 (Fouchier et al., 2005), Netherlands). So, PS4_Supporting is met.
PP4
Variant meets PM2 and is identified in 2 unrelated index cases who fulfill clinical criteria for FH from previous studies (see PS4 for details), after alternative causes of high cholesterol were excluded. So, PP4 is met.
Not Met criteria codes
PM3
No data available.
PM1
Not on exon 4. Not a cysteine residue.
PM4
No in-frame deletions/insertions.
PM5
The variant is the only variant found in this codon.
PM6
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
BA1
FAF= 0.00001663 in African/African American exomes+genomes (gnomAD v4.1.0).
BS4
No data available.
BS3
No data available.
BS1
FAF= 0.00001663 in African/African American exomes+genomes (gnomAD v4.1.0).
BS2
No data available.
BP2
No data available.
BP3
No in-frame deletions/insertions.
BP4
REVEL= 0.564. It is above 0.5.
PS2
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
PS3
No data available.
PS1
The variant is the only variant found in this codon.
PP1
No data available.
PP3
REVEL= 0.564. Functional data on splicing not available. A) variant not on limits. B) variant is exonic and at least 50bp downstream from the canonical acceptor site, but it does not create GT. C) there is no GT nearby. Variant is not predicted to alter splicing.
Curation History
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