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.1300A>C (p.Thr434Pro)

CA404085034

496018 (ClinVar)

Gene: LDLR

Condition: hypercholesterolemia, familial

Inheritance Mode: Semidominant inheritance

Link to MONDO

UUID: a557ff12-b68d-4824-b394-fcd35dc28f70

HGVS expressions

NM_000527.5:c.1300A>C

NM_000527.5(LDLR):c.1300A>C (p.Thr434Pro)

NC_000019.10:g.11113391A>C

CM000681.2:g.11113391A>C

NC_000019.9:g.11224067A>C

CM000681.1:g.11224067A>C

NC_000019.8:g.11085067A>C

NG_009060.1:g.29011A>C

ENST00000558518.6:c.1300A>C

ENST00000252444.9:n.1554A>C

ENST00000455727.6:c.796A>C

ENST00000535915.5:c.1177A>C

ENST00000545707.5:c.919A>C

ENST00000557933.5:c.1300A>C

ENST00000558013.5:c.1300A>C

ENST00000558518.5:c.1300A>C

ENST00000559340.1:n.21A>C

ENST00000560173.1:n.299A>C

ENST00000560467.1:n.780A>C

NM_000527.4:c.1300A>C

NM_001195798.1:c.1300A>C

NM_001195799.1:c.1177A>C

NM_001195800.1:c.796A>C

NM_001195803.1:c.919A>C

NM_001195798.2:c.1300A>C

NM_001195799.2:c.1177A>C

NM_001195800.2:c.796A>C

NM_001195803.2:c.919A>C

Uncertain Significance

PM2 PM5

PS2 PS4 PS3 PS1 PP4 PP1 PP3 BA1 PM6 PM3 PM1 PM4 PVS1 BS2 BS4 BS3 BS1 BP2 BP3 BP4

Evidence Links 0

Expert Panel

Familial Hypercholesterolemia VCEP

Criteria Specification Information

Criteria Specifications for this VCEP

Evidence submitted by expert panel

Familial Hypercholesterolemia VCEP

The NM_000527.5(LDLR):c.1300A>C (p.Thr434Pro) variant is classified as Uncertain significance - insufficient evidence for Familial Hypercholesterolemia by applying evidence codes PM2 and PM5 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). So PM2 is met. PM5: 3 other missense variants in the same codon: - NM_000527.5(LDLR):c.1301C>G (p.Thr434Arg) (ClinVar ID 251774) - Pathogenic by these guidelines - NM_000527.5(LDLR):c.1301C>T (p.Thr434Met)(ClinVar ID 251775) - Unknown significance by these guidelines - NM_000527.5(LDLR):c.1301C>A (p.Thr434Lys) (ClinVar ID 251773) - Likely pathogenic by these guidelines There is 1 variant in the same codon classified as Pathogenic by these guidelines.

PM2

This variant is absent from gnomAD (gnomAD v2.1.1). So PM2 is met.

PM5

3 other missense variants in the same codon: - NM_000527.5(LDLR):c.1301C>G (p.Thr434Arg) (ClinVar ID 251774) - Pathogenic by these guidelines - NM_000527.5(LDLR):c.1301C>T (p.Thr434Met)(ClinVar ID 251775) - Unknown significance by these guidelines - NM_000527.5(LDLR):c.1301C>A (p.Thr434Lys) (ClinVar ID 251773) - Likely pathogenic by these guidelines There is 1 variant in the same codon classified as Pathogenic by these guidelines.

PS2

No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline

PS4

No data available.

PS3

No data available.

PS1

No other missense variant in the same codon with the same amino acid change.

PP4

No data available.

PP1

No data available.

PP3

REVEL= 0.689. It is not above 0.75, so splicing evaluation required. Functional data on splicing not available. A) variant not on limits. B) variant is exonic and at least 50bp upstream from the canonical donor site and does not create AG or GT. C) there is an AG nearby. Wild type score= 6.59. Variant cryptic score= - 4.74, Wild type cryptic score= -10.76; Var criptic/Wt criptic= 0.44, it is below 1.1. Var criptic/Wt score= -0.72, It is below 0.9. Variant is not predicted to alter splicing.

BA1

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

PM6

No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline

PM3

No data available.

PM1

Not in exon 4. Not a cysteine residue.

PM4

No in-frame deletions/insertions

PVS1

Not a null variant

BS2

No data available.

BS4

No data available.

BS3

No data available.

BS1

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

BP2

No data available.

BP3

No in-frame deletions/insertions

BP4

REVEL= 0.689. It is above 0.5. Splicing evaluation required. Functional data on splicing not available. A) variant not on limits. B) variant is exonic and at least 50bp upstream from the canonical donor site and does not create AG or GT.

Approved on: 2022-10-28

Published on: 2022-12-24

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