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.2120A>T (p.Asp707Val)

CA10585780

252227 (ClinVar)

Gene: LDLR
Condition: hypercholesterolemia, familial
Inheritance Mode: Semidominant inheritance
Link to MONDO
UUID: c0d3fbae-235c-4b00-b3f7-a931f508370b
Approved on: 2024-02-23
Published on: 2024-12-02

HGVS expressions

NM_000527.5:c.2120A>T
NM_000527.5(LDLR):c.2120A>T (p.Asp707Val)
NC_000019.10:g.11120502A>T
CM000681.2:g.11120502A>T
NC_000019.9:g.11231178A>T
CM000681.1:g.11231178A>T
NC_000019.8:g.11092178A>T
NG_009060.1:g.36122A>T
ENST00000252444.10:c.2378A>T
ENST00000559340.2:c.*189A>T
ENST00000560467.2:c.2000A>T
ENST00000558518.6:c.2120A>T
ENST00000252444.9:c.2374A>T
ENST00000455727.6:c.1616A>T
ENST00000535915.5:c.1997A>T
ENST00000545707.5:c.1606+269A>T
ENST00000557933.5:c.2120A>T
ENST00000558013.5:c.2120A>T
ENST00000558518.5:c.2120A>T
NM_000527.4:c.2120A>T
NM_001195798.1:c.2120A>T
NM_001195799.1:c.1997A>T
NM_001195800.1:c.1616A>T
NM_001195803.1:c.1606+269A>T
NM_001195798.2:c.2120A>T
NM_001195799.2:c.1997A>T
NM_001195800.2:c.1616A>T
NM_001195803.2:c.1606+269A>T
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Uncertain Significance

Met criteria codes 4
PS4_Supporting PM2 PP4 PP3
Not Met criteria codes 16
BS4 BS3 BS1 BP5 BP7 BP3 BP4 BP1 PVS1 PM5 PM1 PM4 PS3 BA1 PP1 PP2

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
NM_000527.5(LDLR):c.2120A>T (p.Asp707Val) variant is classified as Uncertain significance - insufficient evidence for Familial Hypercholesterolemia by applying 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 23 February 2024. The supporting evidence is as follows: PM2: This variant is absent from gnomAD (gnomAD v2.1.1). PP3: REVEL = 0.964. PS4_Supporting, PP4: Variant meets PM2 and is identified in at least 3 unrelated index cases who fulfill criteria for FH, after alternative causes of high cholesterol were excluded (2 cases with DLCN score >=6 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, France; 1 case with DLCN score >=6 from Robarts Research Institute, Canada).
Met criteria codes
PS4_Supporting
PS4_Supporting: Variant meets PM2 and is identified in at least 3 index cases who fulfill criteria for FH, after alternative causes of high cholesterol were excluded: 2 unrelated index cases with DLCN criteria ≥ 6 from the Centre de Génétique Moléculaire et Chromosomique, Unité de génétique de l'Obésité et des Dyslipidémies (Hôpital de la Pitié-Salpêtrière); plus, 1 index case who fulfills clinical DLCN criteria for FH (DLCN ≥ 6) from Robarts Research Institute.
PM2
- PM2: This variant is absent from gnomAD (gnomAD v2.1.1).
PP4
PP4: Variant meets PM2 and is identified in at least 1 index case who fulfills clinical DLCN criteria for FH (DLCN ≥ 6) from Robarts Research Institute, after alternative causes of high cholesterol were excluded.
PP3
PP3: REVEL = 0.964. It is above 0.75, so PP3 is met.
Not Met criteria codes
BS4
not met, (no information of several index cases or segregation data/cases in different families) only, data from one family from the Centre de Génétique Moléculaire et Chromosomique, Unité de génétique de l'Obésité et des Dyslipidémies (Hôpital de la Pitié-Salpêtrière)
BS3
not met (no information or reports of functional data).
BS1
This variant is absent from gnomAD (gnomAD v2.1.1), therefore BS1 is not met.
BP5
N/A according to FH VCEP Guidelines
BP7
This variant is misense, therefore BP7 is not met.
BP3
N/A according to FH VCEP Guidelines
BP4
BP4: REVEL = 0.964, not bellow 0.50. Therefore, BP4 is not met.
BP1
N/A according to FH VCEP Guidelines
PVS1
This variant is misense, therefore PVS1 is not met.
PM5
NM_000527.5(LDLR):c.2119G>T (p.Asp707Tyr) (ClinVar ID: 252226) considered as Likely Pathogenic by these guidelines NM_000527.5(LDLR):c.2119G>A (p.Asp707Asn) (ClinVar ID: 252225) considered as VUS by these guidelines.
PM1
Variant is not located in exon 4. and does not affect an higly conserved Cys residue.
PM4
This variant is misense, therefore PM4 is not met.
PS3
not met (no information or reports of functional data).
BA1
This variant is absent from gnomAD (gnomAD v2.1.1), therefore BA1 is not met.
PP1
not met, (no information of several index cases or segregation data/cases in different families) only, data from one family from the Centre de Génétique Moléculaire et Chromosomique, Unité de génétique de l'Obésité et des Dyslipidémies (Hôpital de la Pitié-Salpêtrière)
PP2
N/A according to FH VCEP Guidelines
Curation History
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