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]
Link to SEPIO compliant JSON-LD document

Variant: NM_000527.5(LDLR):c.305A>C (p.Gln102Pro)

CA10584836

251127 (ClinVar)

Gene: LDLR
Condition: hypercholesterolemia, familial
Inheritance Mode: Semidominant inheritance
Link to MONDO
UUID: d4dc86ba-b9d7-433f-a758-0af1ddfb4ac7

HGVS expressions

NM_000527.5:c.305A>C
NM_000527.5(LDLR):c.305A>C (p.Gln102Pro)
NC_000019.10:g.11102778A>C
CM000681.2:g.11102778A>C
NC_000019.9:g.11213454A>C
CM000681.1:g.11213454A>C
NC_000019.8:g.11074454A>C
NG_009060.1:g.18398A>C
ENST00000558518.6:c.305A>C
ENST00000252444.9:n.559A>C
ENST00000455727.6:c.305A>C
ENST00000535915.5:c.190+2433A>C
ENST00000545707.5:c.305A>C
ENST00000557933.5:c.305A>C
ENST00000557958.1:n.391A>C
ENST00000558013.5:c.305A>C
ENST00000558518.5:c.305A>C
NM_000527.4:c.305A>C
NM_001195798.1:c.305A>C
NM_001195799.1:c.190+2433A>C
NM_001195800.1:c.305A>C
NM_001195803.1:c.305A>C
NM_001195798.2:c.305A>C
NM_001195799.2:c.190+2433A>C
NM_001195800.2:c.305A>C
NM_001195803.2:c.305A>C

Uncertain Significance

Met criteria codes 2
PP4 PM2
Not Met criteria codes 24
PS3 PS4 PS2 PS1 PP1 PP3 PP2 BA1 PM6 PM3 PM1 PM4 PM5 PVS1 BS2 BS3 BS4 BS1 BP5 BP7 BP2 BP3 BP4 BP1

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

Criteria Specification Approval History
Criteria Specifications for this VCEP
Evidence submitted by expert panel
Familial Hypercholesterolemia VCEP
The NM_000527.5(LDLR):c.305A>C (p.Gln102Pro) variant is classified as Uncertain significance - insufficient evidence for Familial Hypercholesterolemia by applying evidence codes (PM2 and PP4) as defined by the ClinGen Familial Hypercholesterolemia Expert Panel LDLR-specific variant curation guidelines (https://doi.org/10.1016/j.gim.2021.09.012). The supporting evidence is as follows: PM2 - This variant is absent from gnomAD (gnomAD v2.1.1). PP4 - Variant meets PM2 and is identified in at least one case who fufills clinical criteria for FH (see PS4 for details), after alternative causes of high cholesterol were excluded.
Met criteria codes
PP4
Variant meets PM2 and is identified in at least one case who fufills clinical criteria for FH (see PS4 for details), after alternative causes of high cholesterol were excluded.
PM2
This variant is absent from gnomAD (gnomAD v2.1.1).
Not Met criteria codes
PS3
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
PS4
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
PS2
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
PS1
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
PP1
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
PP3
REVEL = 0.652, it is not above 0.75, splicing evaluation required. Scenario A, Acceptor site: The variant is not located at -20 to +3 bases of canonical acceptor splicing site of any exons. Scenario A, Donor site: The variant is not located at -3 to +6 bases of canonical splicing site of any exons. Scenario B, Acceptor site: The variant is not located within the range and does not create de novo AG site. Scenario B, Donor site: The variant is located within range and does not create de novo GT site. Scenario C, Acceptor site: The variant is not located at -20 to +3 bases of intraexonic AG. Scenario C, Donor site: The variant is not located at -3 to +6 bases of intraexonic GT. Interpretation: The variant does not affect splicing.
PP2
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
BA1
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
PM6
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
PM3
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
PM1
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
PM4
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
PM5
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
PVS1
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
BS2
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
BS3
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
BS4
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
BS1
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
BP5
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
BP7
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
BP2
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
BP3
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
BP4
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
BP1
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
Approved on: 2023-04-28
Published on: 2023-04-30
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