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.1946C>T (p.Pro649Leu)

CA10585689

252122 (ClinVar)

Gene: LDLR
Condition: hypercholesterolemia, familial
Inheritance Mode: Semidominant inheritance
Link to MONDO
UUID: ae571234-47e2-4364-bf13-193c26a53c82
Approved on: 2024-10-28
Published on: 2025-01-13

HGVS expressions

NM_000527.5:c.1946C>T
NM_000527.5(LDLR):c.1946C>T (p.Pro649Leu)
NC_000019.10:g.11120192C>T
CM000681.2:g.11120192C>T
NC_000019.9:g.11230868C>T
CM000681.1:g.11230868C>T
NC_000019.8:g.11091868C>T
NG_009060.1:g.35812C>T
ENST00000252444.10:c.2204C>T
ENST00000559340.2:c.*15C>T
ENST00000560467.2:c.1826C>T
ENST00000558518.6:c.1946C>T
ENST00000252444.9:c.2200C>T
ENST00000455727.6:c.1442C>T
ENST00000535915.5:c.1823C>T
ENST00000545707.5:c.1565C>T
ENST00000557933.5:c.1946C>T
ENST00000558013.5:c.1946C>T
ENST00000558518.5:c.1946C>T
ENST00000559340.1:c.527C>T
NM_000527.4:c.1946C>T
NM_001195798.1:c.1946C>T
NM_001195799.1:c.1823C>T
NM_001195800.1:c.1442C>T
NM_001195803.1:c.1565C>T
NM_001195798.2:c.1946C>T
NM_001195799.2:c.1823C>T
NM_001195800.2:c.1442C>T
NM_001195803.2:c.1565C>T
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Uncertain Significance

Met criteria codes 4
PP4 PP3 PM2 PS4_Supporting
Not Met criteria codes 21
PS2 PS1 PS3 BA1 PP1 PP2 PM6 PM5 PM3 PM1 PM4 BS2 BS4 BS3 BS1 BP2 BP3 BP4 BP1 BP7 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.1946C>T (p.Pro649Leu) 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: PopMax MAF = 8.475e-7 (0.00008475%) in European (non-Finnish) (gnomAD v4.1.0). PP3: REVEL = 0.777. PS4_Supporting, PP4: Variant meets PM2 and is identified in at least 2 index cases who fulfill Simon Broome criteria for FH, after alternative causes of high cholesterol were excluded (1 case from Day et al 1997, PMID 9259195; 1 case from Tosi et al 2007, PMID 17094996).
Met criteria codes
PP4
Variant meets PM2 and is identified in at least 1 index case (PMID:9259195) fulfilling Simon Broome criteria for possible/probable/definite FH, after alternative causes of high cholesterol were excluded.
PP3
REVEL = 0.777. It is above 0.75, so PP3 is met.
PM2
This variant is absent from gnomAD (gnomAD v2.1.1). // PopMax MAF = 8.475e-7 (0.00008475%) in European (non-Finnish) (gnomAD v4.1)
PS4_Supporting
Variant meets PM2 and is identified in at least 2 index cases who fulfill criteria for FH, after alternative causes of high cholesterol were excluded: 1 index case fulfilling SB criteria for possible/probable/definite FH from PMID:9259195 // 1 index case fulfilling SB criteria for FH from PMID:17094996.
Not Met criteria codes
PS2
No de novo occurrence
PS1
No other variant with same amino acid change classified as pathogenic
PS3
not met (no information or reports of functional data).
BA1
PM2 is met, therefore BA1 is not met
PP1
not met, (no information of index cases or report of segregation data/cases).
PP2
Not applicable
PM6
No de novo occurrence
PM5
NM_000527.5(LDLR):c.1945C>T (p.Pro649Ser) (ClinVar ID: 252121) considered as VUS by these guidelines
PM3
Variant identified in at least 1 index case with DLCN >=6 that is also carrier of LDLR variant c.858C>A, with no information if in cis/trans, from Centre de Génétique Moléculaire et Chromosomique, Unité de génétique de l'Obésité et des Dyslipidémies (APHP.Sorbonne Université, Hôpital de la Pitié-Salpêtrière). Therefore, this case was not considered // Variant identified in an index case with homozygous FH phenotype and LDLR variant c.2487G>C(p.Gln829His), not confirmed if in cis/trans from PMID:36325061.
PM1
Variant in exon 13 (not exon 4) and does not affect any cysteine residue listed in the guidelines
PM4
Not applicable
BS2
not met, (no information of index cases or report of segregation data/cases).
BS4
No published reports in family members
BS3
not met (no information or reports of functional data).
BS1
PM2 is met, therefore BS1 is not met
BP2
Variant identified in at least 1 index case with DLCN >=6 that is also carrier of LDLR variant c.858C>A, with no information if in cis/trans, from Centre de Génétique Moléculaire et Chromosomique, Unité de génétique de l'Obésité et des Dyslipidémies (APHP.Sorbonne Université, Hôpital de la Pitié-Salpêtrière). Therefore, this case was not considered.
BP3
Not applicable
BP4
REVEL = 0.777, not above 0.5. Therefore, BP4 is met
BP1
Not applicable
BP7
Missense, so not applicable
BP5
Not applicable
Curation History
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