Variant: NM_000527.5(LDLR):c.770G>T (p.Arg257Leu)

CA10585126

251447 (ClinVar)

Gene: LDLR

Condition: hypercholesterolemia, familial

Inheritance Mode: Semidominant inheritance

UUID: 6ce7d3fe-6b00-48c3-a5e1-2e0a0bd8d5f4

Approved on: 2022-08-29

Published on: 2022-12-24

HGVS expressions

NM_000527.5:c.770G>T
NM_000527.5(LDLR):c.770G>T (p.Arg257Leu)
NC_000019.10:g.11106640G>T
CM000681.2:g.11106640G>T
NC_000019.9:g.11217316G>T
CM000681.1:g.11217316G>T
NC_000019.8:g.11078316G>T
NG_009060.1:g.22260G>T
ENST00000558518.6:c.770G>T
ENST00000252444.9:n.1024G>T
ENST00000455727.6:c.314-752G>T
ENST00000535915.5:c.647G>T
ENST00000545707.5:c.389G>T
ENST00000557933.5:c.770G>T
ENST00000558013.5:c.770G>T
ENST00000558518.5:c.770G>T
ENST00000558528.1:n.285G>T
ENST00000560467.1:n.370G>T
NM_000527.4:c.770G>T
NM_001195798.1:c.770G>T
NM_001195799.1:c.647G>T
NM_001195800.1:c.314-752G>T
NM_001195803.1:c.389G>T
NM_001195798.2:c.770G>T
NM_001195799.2:c.647G>T
NM_001195800.2:c.314-752G>T
NM_001195803.2:c.389G>T

Uncertain Significance

• Met criteria codes: PM2

• Not Met criteria codes: BS4 BS3 BS1 BS2 BP5 BP7 BP2 BP3 BP4 BP1 BA1 PVS1 PM6 PM3 PM1 PM4 PM5 PS2 PS4 PS3 PS1 PP1 PP4 PP3 PP2

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.770G>T (p.Arg257Leu) 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 was not identified in gnomAD (gnomAD v2.1.1).

Met criteria codes

• PM2: This variant was not identified in gnomAD (gnomAD v2.1.1)

Not Met criteria codes

• BS4: there is no segregation data
• BS3: there are no functional studies for this variant
• BS1: This variant was not identified in gnomAD (gnomAD v2.1.1)
• BS2: there are no reports of this variant being identified in normolipidemic individuals, so not met
• BP5: not applicable
• BP7: variant is missense, so not met
• BP2: There are no reports of this variant being identified in index cases with other variants, so not met
• BP3: not applicable
• BP4: REVEL = 0.589, it is not below 0.5, so not met
• BP1: not applicable
• BA1: This variant was not identified in gnomAD (gnomAD v2.1.1)
• PVS1: variant is missense and not in initiation codon, so not met
• PM6: There are no reports of this variant being identified de novo, so not met
• PM3: There are no reports of this variant being identified in index cases with other variants, so not met
• PM1: variant is missense and meets PM2, but is not in exon 4 and does not alter Cys, so not met
• PM4: variant is missense, so not met
• PM5: There are 4 other missense variants in the same codon: NM_000527.5(LDLR):c.769C>T (p.Arg257Trp) (ClinVar ID: 251446) - classified as VUS by these guidelines NM_000527.5(LDLR):c.770_771delinsAC (p.Arg257His) (ClinVar ID: 183094) - classified as VUS by these guidelines NM_000527.5(LDLR):c.770G>A (p.Arg257Gln) (ClinVar ID: 927149) - classified as VUS by these guidelines NM_000527.5(LDLR):c.770G>C (p.Arg257Pro) (ClinVar ID: 440602) - classified as VUS by these guidelines so PM5 is not met
• PS2: There are no reports of this variant being identified de novo, so not met
• PS4: variant meets PM2, but there are no reports of this variant being identified in index cases who fulfill clinical FH criteria, so not met
• PS3: there are no functional studies for this variant
• PS1: There are no other variants that lead to the same amino acid change, so not met
• PP1: there is no segregation data
• PP4: variant meets PM2, but there are no reports of this variant being identified in index cases who fulfill clinical FH criteria, so not met
• PP3: REVEL = 0.589, it is not above 0.75, , splicing evaluation required. Functional data on splicing not available. A) not on limits B) variant does not create GT C) there are no GT nearby Variant is not predicted to alter splicing, so PP3 is not met
• PP2: not applicable