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

CA023787

161281 (ClinVar)

Gene: LDLR

Condition: hypercholesterolemia, familial

Inheritance Mode: Semidominant inheritance

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

• Met criteria codes: PP3

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

Expert Panel

Familial Hypercholesterolemia VCEP

Criteria Specification Information

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.

Met criteria codes

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

Not Met criteria codes

• 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
• 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
• 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
• 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.
• 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.
• 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
• PVS1: Missense variant, PVS1 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.