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.1223A>C (p.Glu408Ala)

CA10585363

251739 (ClinVar)

Gene: LDLR

Condition: hypercholesterolemia, familial

Inheritance Mode: Semidominant inheritance

Link to MONDO

UUID: 88c81d65-0f5e-461d-9dad-7e979ad94973

HGVS expressions

NM_000527.5:c.1223A>C

NM_000527.5(LDLR):c.1223A>C (p.Glu408Ala)

NC_000019.10:g.11113314A>C

CM000681.2:g.11113314A>C

NC_000019.9:g.11223990A>C

CM000681.1:g.11223990A>C

NC_000019.8:g.11084990A>C

NG_009060.1:g.28934A>C

ENST00000558518.6:c.1223A>C

ENST00000252444.9:n.1477A>C

ENST00000455727.6:c.719A>C

ENST00000535915.5:c.1100A>C

ENST00000545707.5:c.842A>C

ENST00000557933.5:c.1223A>C

ENST00000558013.5:c.1223A>C

ENST00000558518.5:c.1223A>C

ENST00000560173.1:n.222A>C

ENST00000560467.1:n.703A>C

NM_000527.4:c.1223A>C

NM_001195798.1:c.1223A>C

NM_001195799.1:c.1100A>C

NM_001195800.1:c.719A>C

NM_001195803.1:c.842A>C

NM_001195798.2:c.1223A>C

NM_001195799.2:c.1100A>C

NM_001195800.2:c.719A>C

NM_001195803.2:c.842A>C

Uncertain Significance

PM2 PS4_Supporting PP4 PP3

PS2 PS3 PS1 PM3 PM1 PM4 PM5 PM6 BA1 PVS1 BP5 BP7 BP2 BP3 BP4 BP1 BS4 BS3 BS1 BS2 PP1 PP2

Evidence Links 0

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

PDF

Criteria Specification Approval History

Criteria Specifications for this VCEP

Evidence submitted by expert panel

Familial Hypercholesterolemia VCEP

The NM_000527.5(LDLR):c.1223A>C (p.Glu408Ala) variant is classified as Uncertain significance - insufficient evidence for Familial Hypercholesterolemia by applying evidence codes PM2, PP3, PP4 and PS4_Supporting as defined by the ClinGen Familial Hypercholesterolemia Expert Panel LDLR-specific variant curation guidelines (https://doi.org/10.1101/2021.03.17.21252755). The supporting evidence is as follows: PM2 - This variant was not identified in gnomAD (gnomAD v2.1.1), so PM2 is met. PP3 - REVEL = 0.914. It is above 0.75, so PP3 is met. PP4 - variant meets PM2 and was identified in at least 1 index case with DLCN score of probable FH from U4M - Lille University & CHRU Lille, Université de Lille - CHRU de Lille (SCV000583810.1), France, so PP4 is met. PS4_supporting - variant meets PM2 and was identified in 2 unrelated index cases with SB criteria for FH (total and LDL-cholesterol levels above the 95th percentile of a sex and age-matched French population and autosomal dominant transmission of hypercholesterolemia in the family) from PMID 20809525 (Marduel et al., 2010), France, so PS4_Supporting is met

PM2

This variant was not identified in gnomAD (gnomAD v2.1.1), so PM2 is met

PS4_Supporting

variant meets PM2 and was identified in: - at least 1 index case with DLCN score of probable FH from U4M - Lille University & CHRU Lille, Université de Lille - CHRU de Lille (SCV000583810.1), France - 2 unrelated index cases with SB criteria for FH (total and LDL-cholesterol levels above the 95th percentile of a sex and age-matched French population and autosomal dominant transmission of hypercholesterolemia in the family) from PMID 20809525 (Marduel et al., 2010), France only consider the 2 index cases from PMID 20809525 to avoid double-counting, so PS4_Supporting is met

PP4

PP3

REVEL = 0.914. It is above 0.75, so PP3 is met

PS2

no de novo occurrence, so not met

PS3

no functional study performed, so not met

PS1

no other missense variant leads to the same amino acid change in the same codon, so not met

PM3

not identified in index cases with more than 1 variant

PM1

variant is not in exon 4 and does not alter Cys, so not met

PM4

variant is missense, so not met

PM5

4 other missense variants is the same codon: - NM_000527.5(LDLR):c.1222G>C (p.Glu408Gln) - VUS by these guidelines - NM_000527.5(LDLR):c.1222G>A (p.Glu408Lys) - classified as Likely pathogenic by the FH VCEP, with these guidelines - NM_000527.5(LDLR):c.1223A>T (p.Glu408Val) - Likely pathogenic by these guidelines - NM_000527.5(LDLR):c.1224G>C (p.Glu408Asp) - VUS by these guidelines no variant is classified as Pathogenic by these guidelines, so not met.

PM6

no de novo occurrence, so not met

BA1

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

PVS1

variant is missense and not in initiation codon, so not met

BP5

not applicable

BP7

variant is missense, so not met

BP2

not identified in index cases with more than 1 variant

BP3

not applicable

BP4

REVEL = 0.914. It is not below 0.50, so BP4 is not met

BP1

not applicable

BS4

no segregation data

BS3

no functional study performed, so not met

BS1

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

BS2

not identified in normolipidemic individuals, so not met

PP1

no segregation data

PP2

not applicable

Approved on: 2021-12-16

Published on: 2022-07-11

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