Evidence Repository - Clinical Genome Resources

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

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

CA023446

36454 (ClinVar)

Gene: LDLR

Condition: hypercholesterolemia, familial

Inheritance Mode: Semidominant inheritance

Link to MONDO

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

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

PP4 PP3 PM2 PM3 PM5

BA1 PVS1 PS2 PS4 PS3 PS1 PP1 PP2 PM6 PM1 PM4 BS2 BS4 BS3 BS1 BP2 BP3 BP4 BP1 BP5 BP7

Evidence Links 0

Expert Panel

Familial Hypercholesterolemia VCEP

Criteria Specification Information

Criteria Specifications for this VCEP

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.

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

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

BA1

This variant was not identified in gnomAD (gnomAD v2.1.1), so BA1 is not met

PVS1

variant is missense and not in initiation codon, so 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

PP1

no segregation data

PP2

not applicable

PM6

no de novo occurrence

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

BS2

no data in normolipidemic individuals, so not met

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

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

BP5

not applicable

BP7

variant is missense, so not applicable

Approved on: 2022-08-28

Published on: 2022-08-28

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.