Variant: NM_000527.5(LDLR):c.44T>A (p.Leu15His)

CA10584731

250980 (ClinVar)

Gene: LDLR

Condition: hypercholesterolemia, familial

Inheritance Mode: Semidominant inheritance

UUID: 84851a61-30e9-42f5-b890-0816f6ff06fd

Approved on: 2022-08-28

Published on: 2022-08-28

HGVS expressions

NM_000527.5:c.44T>A
NM_000527.5(LDLR):c.44T>A (p.Leu15His)
NC_000019.10:g.11089592T>A
CM000681.2:g.11089592T>A
NC_000019.9:g.11200268T>A
CM000681.1:g.11200268T>A
NC_000019.8:g.11061268T>A
NG_009060.1:g.5212T>A
ENST00000558518.6:c.44T>A
ENST00000455727.6:c.44T>A
ENST00000535915.5:c.44T>A
ENST00000545707.5:c.44T>A
ENST00000557933.5:c.44T>A
ENST00000557958.1:n.130T>A
ENST00000558013.5:c.44T>A
ENST00000558518.5:c.44T>A
ENST00000560502.5:n.130T>A
NM_000527.4:c.44T>A
NM_001195798.1:c.44T>A
NM_001195799.1:c.44T>A
NM_001195800.1:c.44T>A
NM_001195803.1:c.44T>A
NM_001195798.2:c.44T>A
NM_001195799.2:c.44T>A
NM_001195800.2:c.44T>A
NM_001195803.2:c.44T>A
NR_163945.1:n.68A>T

Uncertain Significance

• Met criteria codes: PM2

• Not Met criteria codes: PVS1 BS2 BS4 BS3 BS1 BP5 BP7 BP2 BP3 BP4 BP1 PS2 PS4 PS3 PS1 PP1 PP4 PP3 PP2 BA1 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 1.1

Evidence submitted by expert panel

Familial Hypercholesterolemia VCEP

The NM_000527.5(LDLR):c.44T>A (p.Leu15His) 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 (gnomAD v2.1.1), so PM2 is met.

Met criteria codes

• PM2: This variant is absent from gnomAD (gnomAD v2.1.1), so PM2 is met.

Not Met criteria codes

• PVS1: variant is missense and not in initiation codon, so not met
• BS2: not identified in normolipidemic individuals, so not met
• BS4: no family data
• BS3: there are no functional studies on this variant
• BS1: This variant is absent from gnomAD (gnomAD v2.1.1), so BS1 is not met.
• BP5: not applicable
• BP7: variant is missense, so not met
• BP2: not identified in cases with other variants
• BP3: not applicable
• BP4: REVEL = 0.749. It is not below 0.50, so BP4 is not met
• BP1: Not applicable
• PS2: no de novo occurrence
• PS4: not identified in index cases fulfilling clinical FH criteria, so not met
• PS3: there are no functional studies on this variant
• PS1: no other missense variant leads to the same amino acid change, so not met
• PP1: no family data
• PP4: not identified in index cases fulfilling clinical FH criteria, so not met
• PP3: REVEL = 0.749. It is not above 0.75, so splicing evaluation is required: A - not on limits B - does not create GT C - there is no GT nearby so PP3 is not met
• PP2: Not applicable
• BA1: This variant is absent from gnomAD (gnomAD v2.1.1), so BA1 is not met.
• PM6: no de novo occurrence
• PM3: not identified in cases with other variants
• PM1: variant is missense and meets PM2, but it is not in exon 4 and does not alter Cys, so not met
• PM4: variant is missense, so not met
• PM5: there is 1 other missense variant in the same codon: NM_000527.5(LDLR):c.44T>C (p.Leu15Pro) - Likely pathogenic so PM5 is not met