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.907C>T (p.Arg303Trp)

CA023787

161281 (ClinVar)

Gene: LDLR

Condition: hypercholesterolemia, familial

Inheritance Mode: Semidominant inheritance

Link to MONDO

UUID: c980a4eb-d83f-4657-b86a-2b67d5862466

Approved on: 2021-06-08

Published on: 2021-06-24

HGVS expressions

NM_000527.5:c.907C>T

NM_000527.5(LDLR):c.907C>T (p.Arg303Trp)

ENST00000558518.6:c.907C>T

ENST00000252444.9:n.1161C>T

ENST00000455727.6:c.403C>T

ENST00000535915.5:c.784C>T

ENST00000545707.5:c.526C>T

ENST00000557933.5:c.907C>T

ENST00000558013.5:c.907C>T

ENST00000558518.5:c.907C>T

ENST00000558528.1:n.422C>T

ENST00000560467.1:n.507C>T

NM_000527.4:c.907C>T

NM_001195798.1:c.907C>T

NM_001195799.1:c.784C>T

NM_001195800.1:c.403C>T

NM_001195803.1:c.526C>T

NM_001195798.2:c.907C>T

NM_001195799.2:c.784C>T

NM_001195800.2:c.403C>T

NM_001195803.2:c.526C>T

NC_000019.10:g.11107481C>T

CM000681.2:g.11107481C>T

NC_000019.9:g.11218157C>T

CM000681.1:g.11218157C>T

NC_000019.8:g.11079157C>T

NG_009060.1:g.23101C>T

Uncertain Significance

PP3

PP4 PP1 PP2 BA1 PM6 PM2 PM3 PM4 PM1 PM5 BS2 BS4 BS3 BS1 PS2 PS4 PS1 PS3 BP2 BP3 BP4 BP1 BP5 BP7 PVS1

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.907C>T (p.Arg303Trp) variant is classified as Uncertain significance - insufficient evidence for Familial Hypercholesterolemia by applying evidence codes (PP3) 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: PP3 - REVEL = 0.815. It is above 0.75, so PP3 is Met.

PP3

REVEL = 0.815. It is above 0.75, so PP3 is Met

PP4

Variant does not meet PM2, so PP4 is Not Met

PP1

no family members were tested, so PP1 is Not Met

PP2

Not applicable

BA1

FAF = 0.0002884 (0.029%) in African/African American exomes (gnomAD v2.1.1). FAF is not above 0.5%, so BA1 is Not Met.

PM6

no de novo cases were identified, so PM6 is Not Met

PM2

PopMax MAF = 0.0004009 (0.04%) in African/African American exomes (gnomAD v2.1.1). MAF is not under 0.02%, so PM2 is Not Met.

PM3

not identified in individuals with other variants, so PM3 is Not Met

PM4

Missense variant, not applicable

PM1

Missense at codon 303. PM2 is Not Met, it is not exon 4 or any of the 60 Cys residues listed, so PM1 is Not Met

PM5

One more missense variant described in same codon: (1)NM_000527.4(LDLR):c.908G>A (p.Arg303Gln) (ClinVar ID 183101) - classified as VUS by these guidelines --- variant classified as VUS, so PM5 is Not Met

BS2

no unaffected individuals identified with the variant, so BS2 is Not Met

BS4

no family members were tested, so BS4 is Not Met

BS3

no functional assays performed, not applicable

BS1

FAF = 0.0002884 (0.029%) in African/African American exomes (gnomAD v2.1.1). FAF is not above 0.2%, so BS1 is Not Met.

PS2

no de novo cases were identified, so PS2 is Not Met

PS4

variant does not meet PM2, so PS4 is Not Met

PS1

No variant described that leads to the same amino acid change, so PS1 is Not Met

PS3

no functional assays performed, not applicable

BP2

not identified in individuals with other variants, so BP2 is Not Met

BP3

Not applicable

BP4

REVEL = 0.815. It is not below 0.15 and PP3 is Met, so BP4 is Not Met

BP1

Not applicable

BP5

Not applicable

BP7

Missense variant, so BP7 is not applicable

PVS1

Missense variant, PVS1 Not Met

The information on this website is not intended for direct diagnostic use or medical decision-making without review by a genetics professional. Individuals should not change their health behavior solely on the basis of information contained on this website. If you have questions about the information contained on this website, please see a health care professional.