Evidence Repository
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
  • See Evidence submitted by expert panel for details.

Variant: NM_000527.5(LDLR):c.757C>T (p.Arg253Trp)

CA023757

161261 (ClinVar)

Gene: LDLR
Condition: hypercholesterolemia, familial
Inheritance Mode: Semidominant inheritance
Link to MONDO
UUID: 903a655a-72bf-4020-8cbb-bf6139c93439

HGVS expressions

NM_000527.5:c.757C>T
NM_000527.5(LDLR):c.757C>T (p.Arg253Trp)
ENST00000558518.6:c.757C>T
ENST00000252444.9:n.1011C>T
ENST00000455727.6:c.314-765C>T
ENST00000535915.5:c.634C>T
ENST00000545707.5:c.376C>T
ENST00000557933.5:c.757C>T
ENST00000558013.5:c.757C>T
ENST00000558518.5:c.757C>T
ENST00000558528.1:n.272C>T
ENST00000560467.1:n.357C>T
NM_000527.4:c.757C>T
NM_001195798.1:c.757C>T
NM_001195799.1:c.634C>T
NM_001195800.1:c.314-765C>T
NM_001195803.1:c.376C>T
NM_001195798.2:c.757C>T
NM_001195799.2:c.634C>T
NM_001195800.2:c.314-765C>T
NM_001195803.2:c.376C>T
NC_000019.10:g.11106627C>T
CM000681.2:g.11106627C>T
NC_000019.9:g.11217303C>T
CM000681.1:g.11217303C>T
NC_000019.8:g.11078303C>T
NG_009060.1:g.22247C>T

Uncertain Significance

The Expert Panel has overridden the computationally generated classification - "[unknown]"
Not Met criteria codes 26
PS2 PS4 PS1 PS3 PP4 PP3 PP2 PP1 PM6 PM2 PM3 PM4 PM1 PM5 PVS1 BA1 BS2 BS4 BS3 BS1 BP2 BP4 BP1 BP3 BP5 BP7

Evidence Links 0

Expert Panel

Criteria Specification Information

Criteria Specifications for this VCEP
Evidence submitted by expert panel
Familial Hypercholesterolemia VCEP
The NM_000527.5(LDLR):c.757C>T (p.Arg253Trp) variant is classified as Uncertain significance - insufficient evidence for Familial Hypercholesterolemia by applying evidence codes (no codes were applied) as defined by the ClinGen Familial Hypercholesterolemia Expert Panel LDLR-specific variant curation guidelines (https://doi.org/10.1101/2021.03.17.21252755).
Not Met criteria codes
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
PP4
Variant does not meet PM2, so PP4 is Not Met
PP3
REVEL = 0.689. It is not above 0.75, splicing evaluation is required. Functional data on splicing not available. A) variant not on limits. B) variant is exonic and at least 50bp downstream from canonical acceptor site and 50 bp upstream of canonical donor, but it does not create GT or AG. C) there is no GT nearby, but there are 2 AG nearby: 1) MES scores: variant cryptic = 3.11, wt cryptic = 1.93, canonical acceptor = 10.79. Ratio variant cryptic/wt cryptic: 3.11/1.93 = 1.611 --- it is above 1.1 Ratio variant cryptic/canonical acceptor: 3.11/10.79 = 0.288 --- it is not above 0.9, so PP3 is Not Met 2) MES scores: variant cryptic = -6.97, wt cryptic = -7.18, canonical acceptor = 10.79. scores are negative, which means they are not used, PP3 is Not Met --- neither AG nearby support PP3, so PP3 is Not Met
PP2
Not applicable
PP1
no family members were tested, so PP1 is Not Met
PM6
no de novo cases were identified, so PM6 is Not Met
PM2
PopMax MAF = 0.001041 (0.1041%) in African/African American exomes (gnomAD v2.1.1). FAF 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 253. PM2 is Not Met, it is not exon 4 or any of the 60 Cys residues listed, so PM1 is Not Met
PM5
Two more missense variants described in same codon: (1)NM_000527.5(LDLR):c.758G>A (p.Arg253Gln) (ClinVar ID 843407) - classified as VUS by these guidelines (2)NM_000527.5(LDLR):c.758G>C (p.Arg253Pro) (ClinVar ID 251435) - classified as VUS by these guidelines --- no variant classified as P, so PM5 is Not Met
PVS1
Missense variant, PVS1 Not Met
BA1
FAF = 0.0008150 (0.082%) in African/African American exomes (gnomAD v2.1.1). FAF is not above 0.5%, so BA1 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 = 0.0008150 (0.082%) in African/African American exomes (gnomAD v2.1.1). FAF is not above 0.2%, so BS1 is Not Met.
BP2
not identified in individuals with other variants, so BP2 is Not Met
BP4
REVEL = 0.689. It is not below 0.15, BP4 is Not Met
BP1
Not applicable
BP3
Not applicable
BP5
Not applicable
BP7
Missense variant, so BP7 is not applicable
Approved on: 2021-06-07
Published on: 2021-06-24
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.
¤ Powered by BCM's Genboree.