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.1945C>T (p.Pro649Ser)

CA10585688

252121 (ClinVar)

Gene: LDLR
Condition: hypercholesterolemia, familial
Inheritance Mode: Semidominant inheritance
Link to MONDO
UUID: 0969c86e-9a9e-4c83-8df7-90c415971ff2
Approved on: 2024-10-28
Published on: 2025-01-13

HGVS expressions

NM_000527.5:c.1945C>T
NM_000527.5(LDLR):c.1945C>T (p.Pro649Ser)
NC_000019.10:g.11120191C>T
CM000681.2:g.11120191C>T
NC_000019.9:g.11230867C>T
CM000681.1:g.11230867C>T
NC_000019.8:g.11091867C>T
NG_009060.1:g.35811C>T
ENST00000252444.10:c.2203C>T
ENST00000559340.2:c.*14C>T
ENST00000560467.2:c.1825C>T
ENST00000558518.6:c.1945C>T
ENST00000252444.9:c.2199C>T
ENST00000455727.6:c.1441C>T
ENST00000535915.5:c.1822C>T
ENST00000545707.5:c.1564C>T
ENST00000557933.5:c.1945C>T
ENST00000558013.5:c.1945C>T
ENST00000558518.5:c.1945C>T
ENST00000559340.1:c.526C>T
NM_000527.4:c.1945C>T
NM_001195798.1:c.1945C>T
NM_001195799.1:c.1822C>T
NM_001195800.1:c.1441C>T
NM_001195803.1:c.1564C>T
NM_001195798.2:c.1945C>T
NM_001195799.2:c.1822C>T
NM_001195800.2:c.1441C>T
NM_001195803.2:c.1564C>T
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Uncertain Significance

Met criteria codes 4
PS4_Supporting PP4 PP3 PM2
Not Met criteria codes 22
BP7 BP5 BP2 BP3 BP4 BP1 PS2 PS1 PS3 PP1 PP2 PVS1 PM6 PM3 PM5 PM1 PM4 BA1 BS2 BS4 BS3 BS1

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.1945C>T (p.Pro649Ser) variant is classified as Uncertain significance - insufficient evidence for Familial Hypercholesterolemia by applying ACMG/AMP evidence codes PM2, PP3, PP4 and PS4_Supporting as defined by the ClinGen Familial Hypercholesterolemia Expert Panel LDLR-specific variant curation guidelines (specification version 1.2) on 28 October 2024. The supporting evidence is as follows: PM2: This variant is absent from gnomAD (gnomAD v4.1.0). PP3: REVEL = 0.766. PS4_Supporting, PP4: Variant meets PM2 and is identified in at least 4 index cases who fulfill criteria for FH, after alternative causes of high cholesterol were excluded (1 case with probable FH by Simon Broome criteria and 1 case with DLCN score >=6 from Centre de Génétique Moléculaire et Chromosomique, Unité de génétique de l'Obésité et des Dyslipidémies, APHP.Sorbonne Université, Hôpital de la Pitié-Salpêtrière, France; 1 case with DLCN score >=6 from Research Lab of Molecular Genetics of Lipid Metabolism, Italy - Prof. M. Arca; 1 case with DLCN score >=6 from Meshkov et al 2021, PMID 33418990).
Met criteria codes
PS4_Supporting
Variant meets PM2 and is identified in at least 4 index cases who fulfill criteria for FH, after alternative causes of high cholesterol were excluded: 2 index cases from Centre de Génétique Moléculaire et Chromosomique (one fullfiling SB criteria for probable FH and other fulfilling DLCN>=6) // 1 index case fulfilling DLCN>=6 from the Research Lab of Molecular Genetics of Lipid Metabolism // 1 index case fulfilling DLCN>=6 from PMID:33418990.
PP4
Variant meets PM2 and is identified in at least 1 index case fulfilling FH criteria (DLCN <=6), after alternative causes of high cholesterol were excluded, from Centre de Génétique Moléculaire et Chromosomique, Unité de génétique de l'Obésité et des Dyslipidémies (APHP.Sorbonne Université, Hôpital de la Pitié-Salpêtrière)
PP3
REVEL = 0.766. It is above 0.75, so PP3 is met.
PM2
This variant is absent from gnomAD (gnomAD v2.1.1 and v4.1).
Not Met criteria codes
BP7
Missense variant
BP5
Not applicable
BP2
Not identified in index cases with more than one variant
BP3
Missense variant
BP4
REVEL is not below 0.5
BP1
Not applicable
PS2
No de novo occurrence
PS1
No other variant with same amino acid change
PS3
not met (no information or reports of functional data).
PP1
Variant segregates with FH phenotype in 1 relative positive for variant with LDL-C >75th percentile from the Centre de Génétique Moléculaire et Chromosomique, Unité de génétique de l'Obésité et des Dyslipidémies (APHP.Sorbonne Université, Hôpital de la Pitié-Salpêtrière) (not in at least 2 informative meiosis, so PP1 is not met)
PP2
Not applicable
PVS1
Missense variant
PM6
No de novo occurrence
PM3
Not identified in index cases with more than one variant
PM5
NM_000527.5(LDLR):c.1946C>T (p.Pro649Leu) (ClinVar ID: 252122) considered as VUS by these guidelines.
PM1
Variant located on exon 13 (not exon 4) and does not affect any cysteine residues listed on the FH VCEP guidelines
PM4
Missense variant
BA1
This variant is absent from gnomAD (gnomAD v2.1.1 and v4.1).
BS2
Not identified in normolipidemic individuals
BS4
No non-segregation identified.
BS3
not met (no information or reports of functional data).
BS1
This variant is absent from gnomAD (gnomAD v2.1.1 and v4.1).
Curation History
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