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]

Variant: NM_000527.5(LDLR):c.915G>C (p.Trp305Cys)

Curation Version - 1.0
Curation History
JSON LD for Version 1.0

CA10585191

251521 (ClinVar)

Gene: LDLR

Condition: hypercholesterolemia, familial

Inheritance Mode: Semidominant inheritance

Link to MONDO

UUID: 55d2766b-b6d9-4ca6-ac05-42b8f3b63dc6

Approved on: 2023-04-28

Published on: 2023-04-30

HGVS expressions

NM_000527.5:c.915G>C

NM_000527.5(LDLR):c.915G>C (p.Trp305Cys)

NC_000019.10:g.11107489G>C

CM000681.2:g.11107489G>C

NC_000019.9:g.11218165G>C

CM000681.1:g.11218165G>C

NC_000019.8:g.11079165G>C

NG_009060.1:g.23109G>C

ENST00000558518.6:c.915G>C

ENST00000252444.9:n.1169G>C

ENST00000455727.6:c.411G>C

ENST00000535915.5:c.792G>C

ENST00000545707.5:c.534G>C

ENST00000557933.5:c.915G>C

ENST00000558013.5:c.915G>C

ENST00000558518.5:c.915G>C

ENST00000558528.1:n.430G>C

ENST00000560467.1:n.515G>C

NM_000527.4:c.915G>C

NM_001195798.1:c.915G>C

NM_001195799.1:c.792G>C

NM_001195800.1:c.411G>C

NM_001195803.1:c.534G>C

NM_001195798.2:c.915G>C

NM_001195799.2:c.792G>C

NM_001195800.2:c.411G>C

NM_001195803.2:c.534G>C

Uncertain Significance

PM2 PP4 PP3

PM3 PM1 PM4 PM5 PM6 BS2 BS4 BS3 BS1 BP2 BP3 BP4 BA1 PS2 PS3 PS1 PP1 PVS1

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.915G>C (p.Trp305Cys) variant is classified as Uncertain significance - insufficient evidence 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/10.1016/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. PP3: REVEL=0.91. It is above 0.75, so PP3 is met. PP4: Variant meets PM2, and is identified in 1 case from 16250003, after alternative causes of high cholesterol were excluded. So, PP4 is met.

PM2

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

PP4

Variant meets PM2, and is identified in 1 case from 16250003, after alternative causes of high cholesterol were excluded. So, PP4 is met.

PP3

REVEL=0.91. It is above 0.75, so PP3 is met.

PM3

No data available

PM1

Not on exon 4. Not a cysteine residue.

PM4

No in-frame deletions/insertions

PM5

1 other missense variant in the same codon: NM_000527.5(LDLR):c.914G>C (p.Trp305Ser) (ClinVar ID 251519) Uncertain significance by these guidelines. No other pathogenic missense variants in the same codon.

PM6

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

BS2

No data available

BS4

No data available

BS3

No functional studies available.

BS1

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

BP2

No data available

BP3

No in-frame deletions/insertions

BP4

REVEL=0.91. It is above 0.5

BA1

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

PS2

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

PS3

No functional studies available.

PS1

One more missense variant that leads to the same amino acid change: NM_000527.5(LDLR):c.915G>T (p.Trp305Cys) (ClinVar ID 1437514) Uncertain significance by these guidelines.

PP1

No data available

PVS1

Not a null variant

Curation History

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