Evidence Repository - Clinical Genome Resources

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.1185G>C (p.Val395=)

CA10585340

251702 (ClinVar)

Gene: LDLR

Condition: hypercholesterolemia, familial

Inheritance Mode: Semidominant inheritance

Link to MONDO

UUID: fabb44c4-f72c-4054-ac93-c7938f486121

HGVS expressions

NM_000527.5:c.1185G>C

NM_000527.5(LDLR):c.1185G>C (p.Val395=)

NC_000019.10:g.11111638G>C

CM000681.2:g.11111638G>C

NC_000019.9:g.11222314G>C

CM000681.1:g.11222314G>C

NC_000019.8:g.11083314G>C

NG_009060.1:g.27258G>C

ENST00000558518.6:c.1185G>C

ENST00000252444.9:n.1439G>C

ENST00000455727.6:c.681G>C

ENST00000535915.5:c.1062G>C

ENST00000545707.5:c.804G>C

ENST00000557933.5:c.1185G>C

ENST00000558013.5:c.1185G>C

ENST00000558518.5:c.1185G>C

ENST00000560173.1:n.184G>C

ENST00000560467.1:n.665G>C

NM_000527.4:c.1185G>C

NM_001195798.1:c.1185G>C

NM_001195799.1:c.1062G>C

NM_001195800.1:c.681G>C

NM_001195803.1:c.804G>C

NM_001195798.2:c.1185G>C

NM_001195799.2:c.1062G>C

NM_001195800.2:c.681G>C

NM_001195803.2:c.804G>C

Likely Benign

The Expert Panel has overridden the computationally generated classification - "Uncertain Significance - Conflicting Evidence"

BP7 BP4 PM2

PVS1 BS2 BS4 BS3 BS1 BP5 BP2 BP3 BP1 PS2 PS4 PS3 PS1 BA1 PP4 PP1 PP3 PP2 PM6 PM3 PM1 PM4 PM5

Evidence Links 0

Expert Panel

Familial Hypercholesterolemia VCEP

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.1185G>C (p.Val395=) variant is classified as Likely benign for Familial Hypercholesterolemia by applying evidence codes (PM2, BP4 and BP7) 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). BP4 - No REVEL available, splicing evaluation needed. Functional data on splicing not available. A) variant is located at -3 to +6 bases of canonical donor splicing site. MES scores: de novo donor = 9.1, authentic donor = 7.23. Ratio variant/wt = 1.26. It is above 1.0. Score ≥ 1.0 is supportive evidence of benign. B) The variant is located within range but does not create de novo GT site. C) Variant not on limits. Variant is not predicted to alter splicing. So BP4 is met. BP7 - Variant is synonymous and meets BP4.

BP7

Variant is synonymous and meets BP4.

BP4

No REVEL available, splicing evaluation needed. Functional data on splicing not available. A) variant is located at -3 to +6 bases of canonical donor splicing site. MES scores: de novo donor = 9.1, authentic donor = 7.23. Ratio variant/wt = 1.26. It is above 1.0. Score ≥ 1.0 is supportive evidence of benign. B) The variant is located within range but does not create de novo GT site. C) Variant not on limits. Variant is not predicted to alter splicing. So BP4 is met.

PM2

This variant is absent from gnomAD (gnomAD v2.1.1).

PVS1