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]
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  • See Evidence submitted by expert panel for details.

Variant: NM_000527.5(LDLR):c.2389+4A>G

CA040267

252304 (ClinVar)

Gene: LDLR
Condition: hypercholesterolemia, familial
Inheritance Mode: Semidominant inheritance
Link to MONDO
UUID: 22d1d840-50cb-4d47-b68c-7e1b458094c2
Approved on: 2021-06-22
Published on: 2021-06-24

HGVS expressions

NM_000527.5:c.2389+4A>G
NM_000527.5(LDLR):c.2389+4A>G
NC_000019.10:g.11128089A>G
CM000681.2:g.11128089A>G
NC_000019.9:g.11238765A>G
CM000681.1:g.11238765A>G
NC_000019.8:g.11099765A>G
NG_009060.1:g.43709A>G
ENST00000558518.6:c.2389+4A>G
ENST00000252444.9:n.2643+4A>G
ENST00000455727.6:c.1885+4A>G
ENST00000535915.5:c.2266+4A>G
ENST00000545707.5:c.1855+4A>G
ENST00000557933.5:c.2389+4A>G
ENST00000558013.5:c.2389+4A>G
ENST00000558518.5:c.2389+4A>G
ENST00000560628.1:n.108+435A>G
NM_000527.4:c.2389+4A>G
NM_001195798.1:c.2389+4A>G
NM_001195799.1:c.2266+4A>G
NM_001195800.1:c.1885+4A>G
NM_001195803.1:c.1855+4A>G
NM_001195798.2:c.2389+4A>G
NM_001195799.2:c.2266+4A>G
NM_001195800.2:c.1885+4A>G
NM_001195803.2:c.1855+4A>G

Uncertain Significance

Met criteria codes 3
PP4 PP3 PM2
Not Met criteria codes 23
PS2 PS4 PS3 PS1 PP1 PP2 PM3 PM1 PM4 PM5 PM6 BA1 BS2 BS4 BS3 BS1 BP2 BP3 BP4 BP1 BP5 BP7 PVS1

Evidence Links 0

Expert Panel

Criteria Specification Information

Criteria Specifications for this VCEP
Evidence submitted by expert panel
Familial Hypercholesterolemia VCEP
NM_000527.5(LDLR):c.2389+4A>G variant is classified as variant of Uncertain significance for Familial Hypercholesterolemia by applying evidence codes (PM2, PP3 and PP4) as defined by the ClinGen Familial Hypercholesterolemia Expert Panel LDLR-specific variant curation guidelines (https://doi.org/10.1101/2021.03.17.21252755). The supporting evidence is as follows: PM2 - PopMax MAF = 0.000008798 (0.0009%) in European non-Finnish (gnomAD v2.1.1). PP3 - No REVEL, splicing evaluation required. Functional data on splicing not available. A) variant located at -3 to +6 from canonical donor splice site Ratio variant/wt canonical acceptor/donor = 0,786004057 ---- It is below 0.8 PP4 - Variant meets PM2. Identified in 1 FH case from Ambry Genetics who fulfills Simon-Broome criteria.
Met criteria codes
PP4
Variant meets PM2. Identified in 1 FH case from Ambry Genetics who fulfills Simon-Broome criteria.
PP3
No REVEL, splicing evaluation required. Functional data on splicing not available. A) variant located at -3 to +6 from canonical donor splice site Ratio variant/wt canonical acceptor/donor = 0,786004057 ---- It is below 0.8
PM2
PopMax MAF = 0.000008798 (0.0009%) in European non-Finnish (gnomAD v2.1.1). MAF is below 0.02%.
Not Met criteria codes
PS2
No de novo cases were identified.
PS4
Variant meets PM2. Variant identified only in 1 index cases fulfills Simon-Broome criteria (Ambry Genetics laboratory). At least 2 cases are needed - PS4 is not met.
PS3
No functional assays performed/found - not applicable.
PS1
Intronic variant. Not applicable.
PP1
No family members tested.
PP2
Not applicable.
PM3
Not identified in individuals with other variants.
PM1
Intronic variant. Not applicable
PM4
Intronic variant. Not applicable.
PM5
Intronic variant. Not applicable.
PM6
No de novo cases were identified.
BA1
no FAF, just total MAF = 0.000003978 (0.0004%) in European non-Finnish (gnomAD v2.1.1). MAF is not above 0.5%
BS2
No unaffected individuals identified with the variant.
BS4
No family members tested.
BS3
No functional assays performed/found - not applicable.
BS1
no FAF, just total MAF = 0.000003978 (0.0004%) in European non-Finnish (gnomAD v2.1.1). MAF is not above 0.2%
BP2
Not identified in individuals with other variants.
BP3
Not applicable.
BP4
No REVEL, splicing evaluation required. Functional data on splicing not available. A) variant located at -3 to +6 from canonical donor splice site Ratio variant/wt canonical acceptor/donor = 0,786004057 ---- It is not above 1.0
BP1
Not applicable.
BP5
Not applicable.
BP7
Intronic variant. Not applicable.
PVS1
Intronic variant outside the canonical +/- 1 or 2 splice sites. Not applicable.
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