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.2119G>T (p.Asp707Tyr)

CA10585779

252226 (ClinVar)

Gene: LDLR
Condition: hypercholesterolemia, familial
Inheritance Mode: Semidominant inheritance
Link to MONDO
UUID: 05dee778-3f4a-4e23-8d1a-68df344f18e5
Approved on: 2024-02-23
Published on: 2024-12-02

HGVS expressions

NM_000527.5:c.2119G>T
NM_000527.5(LDLR):c.2119G>T (p.Asp707Tyr)
NC_000019.10:g.11120501G>T
CM000681.2:g.11120501G>T
NC_000019.9:g.11231177G>T
CM000681.1:g.11231177G>T
NC_000019.8:g.11092177G>T
NG_009060.1:g.36121G>T
ENST00000252444.10:c.2377G>T
ENST00000559340.2:c.*188G>T
ENST00000560467.2:c.1999G>T
ENST00000558518.6:c.2119G>T
ENST00000252444.9:c.2373G>T
ENST00000455727.6:c.1615G>T
ENST00000535915.5:c.1996G>T
ENST00000545707.5:c.1606+268G>T
ENST00000557933.5:c.2119G>T
ENST00000558013.5:c.2119G>T
ENST00000558518.5:c.2119G>T
NM_000527.4:c.2119G>T
NM_001195798.1:c.2119G>T
NM_001195799.1:c.1996G>T
NM_001195800.1:c.1615G>T
NM_001195803.1:c.1606+268G>T
NM_001195798.2:c.2119G>T
NM_001195799.2:c.1996G>T
NM_001195800.2:c.1615G>T
NM_001195803.2:c.1606+268G>T
More

Likely Pathogenic

Met criteria codes 4
PS3 PP4 PP3 PM2
Not Met criteria codes 17
PVS1 BA1 BS2 BS4 BS3 BS1 BP3 BP4 BP1 BP5 BP7 PS4 PP1 PP2 PM5 PM1 PM4

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.2119G>T (p.Asp707Tyr) variant is classified as Likely Pathogenic for Familial Hypercholesterolemia by applying ACMG/AMP evidence codes PS3, PM2, PP3 and PP4 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 = 0.973. PS3: Level 1 functional studies performed using heterologous cells (CHO) with Western blot and flow cytometry, showed <2% cell surface expression, 2% binding and 6% uptake, reported in PMID 32015373 (Galicia-Garcia et al., 2020). Activity is below 70% of wild-type, consistent with damaging effect. PP4: Variant meets PM2 and is identified in at least 1 index case with DLCN score >=6 after alternative causes of high cholesterol were excluded, reported in PMID 19318025 (Alonso et al., 2009).
Met criteria codes
PS3
- PS3: Functional studies (PMID: 32015373) performed using Heterologous cells (CHO), WB and FACS - results - <2% cell surface, 2% binding and 6% uptake. Activity is below 70% of wild-type, so functional study is consistent with damaging effect. Therefore, PS3 is met.
PP4
- PP4: Variant meets PM2 and is identified in at least 1 index case (PMID:19318025) fulfilling clinical DLCN criteria ≥ 6, after alternative causes of high cholesterol were excluded.
PP3
PP3: REVEL = 0.973. It is above 0.75, so PP3 is met.
PM2
- PM2: This variant is absent from gnomAD (gnomAD v2.1.1).
Not Met criteria codes
PVS1
This variant is misense, therefore PVS1 is not met.
BA1
This variant is absent from gnomAD (gnomAD v2.1.1), therefore BA1 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
Functional studies (PMID: 32015373) are consistent with damaging effect. Therefore, BS3 is not met
BS1
This variant is absent from gnomAD (gnomAD v2.1.1), therefore BS1 is not met.
BP3
N/A according to FH VCEP Guidelines
BP4
BP4: REVEL = 0.973, not bellow 0.50. Therefore, BP4 is not met.
BP1
N/A according to FH VCEP Guidelines
BP5
N/A according to FH VCEP Guidelines
BP7
This variant is misense, therefore BP7 is not met.
PS4
not met, (no information of index cases or report of segregation data/cases).
PP1
not met, (no information of index cases or report of segregation data/cases).
PP2
N/A according to FH VCEP Guidelines
PM5
NM_000527.5(LDLR):c.2119G>A (p.Asp707Asn) (ClinVar ID: 252225) considered as VUS by these guidelines. NM_000527.5(LDLR):c.2120A>T (p.Asp707Val) (ClinVar ID: 252227) 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.
Curation History
The information on this website is not intended for direct diagnostic use or medical decision-making without review by a genetics professional. Individuals should not change their health behavior solely on the basis of information contained on this website. If you have questions about the information contained on this website, please see a health care professional.
¤ Powered by BCM's Genboree.