Variant: NM_000527.5(LDLR):c.1210A>T (p.Thr404Ser)

CA404084697

431523 (ClinVar)

Gene: LDLR

Condition: hypercholesterolemia, familial

Inheritance Mode: Semidominant inheritance

UUID: 3821187e-65d0-45d6-a043-bfd78030e474

HGVS expressions

NM_000527.5:c.1210A>T
NM_000527.5(LDLR):c.1210A>T (p.Thr404Ser)
NC_000019.10:g.11113301A>T
CM000681.2:g.11113301A>T
NC_000019.9:g.11223977A>T
CM000681.1:g.11223977A>T
NC_000019.8:g.11084977A>T
NG_009060.1:g.28921A>T
ENST00000558518.6:c.1210A>T
ENST00000252444.9:n.1464A>T
ENST00000455727.6:c.706A>T
ENST00000535915.5:c.1087A>T
ENST00000545707.5:c.829A>T
ENST00000557933.5:c.1210A>T
ENST00000558013.5:c.1210A>T
ENST00000558518.5:c.1210A>T
ENST00000560173.1:n.209A>T
ENST00000560467.1:n.690A>T
NM_000527.4:c.1210A>T
NM_001195798.1:c.1210A>T
NM_001195799.1:c.1087A>T
NM_001195800.1:c.706A>T
NM_001195803.1:c.829A>T
NM_001195798.2:c.1210A>T
NM_001195799.2:c.1087A>T
NM_001195800.2:c.706A>T
NM_001195803.2:c.829A>T

Uncertain Significance

• Met criteria codes: PM2

• Not Met criteria codes: PVS1 BA1 BS2 BS3 BS1 BP7 BP2 BP4 PS2 PS4 PS3 PS1 PP4 PP3 PM6 PM3 PM1 PM4 PM5

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

Evidence submitted by expert panel

Familial Hypercholesterolemia VCEP

The NM_000527.5(LDLR):c.1210A>T (p.Thr404Ser) variant is classified as Uncertain significance - insufficient evidence for Familial Hypercholesterolemia by applying evidence code PM2 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 v2.1.1

Met criteria codes

• PM2: This variant is absent from gnomAD v2.1.1

Not Met criteria codes

• PVS1: Not a null variant.
• BA1: This variant is absent from gnomAD v2.1.1
• BS2: No data.
• BS3: No functional data.
• BS1: This variant is absent from gnomAD v2.1.1
• BP7: Not a synonymous variant.
• BP2: No data.
• BP4: REVEL = 0.728
• PS2: Not met.
• PS4: Not met.
• PS3: No functional data.
• PS1: Not met.
• PP4: Not met.
• PP3: REVEL = 0.728 Scenario A, Acceptor site: The variant is not located at -20 to +3 bases of canonical acceptor splicing site of any exons. Scenario A, Donor site: The variant is not located at -3 to +6 bases of canonical donor splicing site of any exons. Scenario B, Acceptor site: The variant is located within the range but does not create denovo AG site. Scenario B, Donor site: The variant is out of range. No need to studying denovo GT site. Scenario C, Acceptor site: The variant is within the range and does not create a denovo AG. There is a AG site in downstream (20 Nt). Wild type canonical acceptor motif: CTCGCTCCCCGGACCCCCAGGCT: 6.59 Wild type cryptic acceptor motif (downstream): TCTTCACCAACCGGCACGAGGTC: -10.44 Variant cryptic acceptor motif (downstream): TCTTCTCCAACCGGCACGAGGTC: -8.58 Var cryptic/Wt cryptic = 0.82 Var cryptic/Wt canonical = -1.3 Scenario C, Donor site: The variant is out of range. No need to studying nearby GT site. Interpretation: The variant does not affect splicing process.
• PM6: Not met.
• PM3: No data.
• PM1: Not located in exon 4 or at a cysteine residue.
• PM4: Not an in-frame deletion or insertion.
• PM5: Not met.

Approved on: 2023-04-28

Published on: 2023-05-01