Variant: NM_000527.5(LDLR):c.1291G>C (p.Ala431Pro)

CA023446

36454 (ClinVar)

Gene: LDLR

Condition: hypercholesterolemia, familial

Inheritance Mode: Semidominant inheritance

UUID: e84a20c0-138d-4529-b5ae-386ecfbc2a26

Approved on: 2022-08-28

Published on: 2022-08-28

HGVS expressions

NM_000527.5:c.1291G>C
NM_000527.5(LDLR):c.1291G>C (p.Ala431Pro)
NC_000019.10:g.11113382G>C
CM000681.2:g.11113382G>C
NC_000019.9:g.11224058G>C
CM000681.1:g.11224058G>C
NC_000019.8:g.11085058G>C
NG_009060.1:g.29002G>C
ENST00000558518.6:c.1291G>C
ENST00000252444.9:n.1545G>C
ENST00000455727.6:c.787G>C
ENST00000535915.5:c.1168G>C
ENST00000545707.5:c.910G>C
ENST00000557933.5:c.1291G>C
ENST00000558013.5:c.1291G>C
ENST00000558518.5:c.1291G>C
ENST00000559340.1:n.12G>C
ENST00000560173.1:n.290G>C
ENST00000560467.1:n.771G>C
NM_000527.4:c.1291G>C
NM_001195798.1:c.1291G>C
NM_001195799.1:c.1168G>C
NM_001195800.1:c.787G>C
NM_001195803.1:c.910G>C
NM_001195798.2:c.1291G>C
NM_001195799.2:c.1168G>C
NM_001195800.2:c.787G>C
NM_001195803.2:c.910G>C

Likely Pathogenic

• Met criteria codes: PP4 PP3 PM3 PM5 PM2

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

Expert Panel

Familial Hypercholesterolemia VCEP

Criteria Specification Information

Evidence submitted by expert panel

Familial Hypercholesterolemia VCEP

The NM_000527.5(LDLR):c.1291G>C (p.Ala431Pro) variant is classified as Likely pathogenic for Familial Hypercholesterolemia by applying evidence codes PM2, PM3, PM5, PP3 and PP4, 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), so PM2 is met. PM3 - variant meets PM2 and was identified in: - index case who is homozygous for the variant and has LDL at least 550mg/dl (figure 2A in the paper) from PMID 29502162 (Klaus et al. 2018), Germany. --- individual is homozygous for variant and has an homozygous phenotype, so PM3 is met. PM5 - one other missense variant in the same codon: - NM_000527.5(LDLR):c.1291G>A (p.Ala431Thr) - 2 stars, Pathogenic/Likely pathogenic​ in ClinVar - Pathogenic by these guidelines, so PM5 is met. PP3 - REVEL = 0.939. It is above 0.75, so PP3 is met. PP4 - variant meets PM2 and was identified in 1 index case with DLCN at least 8 (untreated LDL at least 550mg/dl) from PMID 29502162 (Klaus et al., 2018), Germany, so PP4 is met.

Met criteria codes

• PP4: variant meets PM2 and was identified in: - 1 index case with DLCN at least 8 (untreated LDL at least 550mg/dl) from PMID 29502162 (Klaus et al., 2018), Germany. so PP4 is met
• PP3: REVEL = 0.939. It is above 0.75, so PP3 is met
• PM3: variant meets PM2 and was identified in: - index case who is homozygous for the variant and has LDL at least 550mg/dl (figure 2A in the paper) from PMID 29502162 (Klaus et al. 2018), Germany. --- individual is homozygous for variant and has an homozygous phenotype, so PM3 is met
• PM5: one other missense variant in the same codon: - NM_000527.5(LDLR):c.1291G>A (p.Ala431Thr) - 2 stars, Pathogenic/Likely pathogenic​ in ClinVar - Pathogenic by these guidelines, so PM5 is met
• PM2: This variant was not identified in gnomAD (gnomAD v2.1.1), so PM2 is met

Not Met criteria codes

• BS4: no segregation data
• BS3: no functional study on this variant
• BS1: This variant was not identified in gnomAD (gnomAD v2.1.1), so BS1 is not met
• BS2: no data in normolipidemic individuals, so not met
• PVS1: variant is missense and not in initiation codon, so not applicable
• BP5: not applicable
• BP7: variant is missense, so not applicable
• BP2: variant was not identified in index cases with other variants
• BP3: not applicable
• BP4: REVEL = 0.939. It is not below 0.50, so BP4 is not met
• BP1: not applicable
• PS2: no de novo occurrence
• PS4: variant meets PM2 and was identified in: - 1 index case with DLCN at least 8 (untreated LDL at least 550mg/dl) from PMID 29502162 (Klaus et al., 2018), Germany. not enough, so PS4 is not met
• PS3: no functional study on this variant
• PS1: no other variant leads to the same amino acid change, so not met
• BA1: This variant was not identified in gnomAD (gnomAD v2.1.1), so BA1 is not met
• PP1: no segregation data
• PP2: not applicable
• PM1: variant is missense and PM2 is met, but it is not in exon 4 and does not alter Cys, so not met
• PM4: variant is missense, so not applicable
• PM6: no de novo occurrence