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.1224G>C (p.Glu408Asp)

CA305300066

431524 (ClinVar)

Gene: LDLR

Condition: hypercholesterolemia, familial

Inheritance Mode: Semidominant inheritance

Link to MONDO

UUID: 31756985-70c6-4aee-a6a1-1577d6d53515

HGVS expressions

NM_000527.5:c.1224G>C

NM_000527.5(LDLR):c.1224G>C (p.Glu408Asp)

NC_000019.10:g.11113315G>C

CM000681.2:g.11113315G>C

NC_000019.9:g.11223991G>C

CM000681.1:g.11223991G>C

NC_000019.8:g.11084991G>C

NG_009060.1:g.28935G>C

ENST00000558518.6:c.1224G>C

ENST00000252444.9:n.1478G>C

ENST00000455727.6:c.720G>C

ENST00000535915.5:c.1101G>C

ENST00000545707.5:c.843G>C

ENST00000557933.5:c.1224G>C

ENST00000558013.5:c.1224G>C

ENST00000558518.5:c.1224G>C

ENST00000560173.1:n.223G>C

ENST00000560467.1:n.704G>C

NM_000527.4:c.1224G>C

NM_001195798.1:c.1224G>C

NM_001195799.1:c.1101G>C

NM_001195800.1:c.720G>C

NM_001195803.1:c.843G>C

NM_001195798.2:c.1224G>C

NM_001195799.2:c.1101G>C

NM_001195800.2:c.720G>C

NM_001195803.2:c.843G>C

Uncertain Significance

BP4 PM2

BA1 PVS1 BS4 BS3 BS1 BS2 BP5 BP7 BP2 BP3 BP1 PS2 PS4 PS1 PS3 PP1 PP4 PP3 PP2 PM3 PM1 PM4 PM5 PM6

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.1224G>C (p.Glu408Asp) variant is classified as Uncertain significance - insufficient evidence for Familial Hypercholesterolemia by applying evidence PM2 and BP4 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. BP4 - REVEL = 0.414. It is below 0.50, splicing evaluation required. Functional data on splicing not available. A) not on limits B) does not create AG Variant is not predicted to alter splicing, so BP4 is met

BP4

REVEL = 0.414. It is below 0.50, splicing evaluation required. Functional data on splicing not available. A) not on limits B) does not create AG Variant is not predicted to alter splicing, so BP4 is met

PM2

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

BS4

no case 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

BP5

not applicable

BP7

variant is missense, so not met

BP2

no case data

BP3

not applicable

BP1

not applicable

PS2

no de novo occurrence

PS4

variant meets PM2, but there are no case data, so not met

PS1

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

PS3

no functional study performed, so not met

PP1

no case data

PP4

variant meets PM2, but there are no case data, so not met

PP3

REVEL = 0.414. It is not above 0.75, splicing evaluation required. Functional data on splicing not available. A) not on limits B) does not create AG C) variant is exonic and there are 2 AGs nearby: 1) variant cryptic acceptor (ACCAACCGGCACGACGTCAGGAA) MES scores: variant cryptic = -0.81, wt cryptic = -4.18, canonical acceptor = 6.59. Both variant and wt cryptic scores are negative, so they are not used 2) variant cryptic acceptor (ACCGGCACGACGTCAGGAAGATG) MES scores: variant cryptic = -9.07, wt cryptic = -14.27, canonical acceptor = 6.59. Both variant and wt cryptic scores are negative, so they are not used Variant is not predicted to alter splicing, so PP3 is not met

PP2

not applicable

PM3

no case data

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.1223A>C (p.Glu408Ala) - VUS by these guidelines no variant is classified as Pathogenic by these guidelines, so not met.

PM6

no de novo occurrence

Approved on: 2021-12-16

Published on: 2022-07-11

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