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]

Variant: NM_000527.5(LDLR):c.1222G>C (p.Glu408Gln)

Curation Version - 1.1
Curation History
JSON LD for Version 1.1

CA16043073

373430 (ClinVar)

Gene: LDLR

Condition: hypercholesterolemia, familial

Inheritance Mode: Semidominant inheritance

Link to MONDO

UUID: 27482e34-21b2-4832-8533-6a02443850b0

Approved on: 2021-12-16

Published on: 2022-07-11

HGVS expressions

NM_000527.5:c.1222G>C

NM_000527.5(LDLR):c.1222G>C (p.Glu408Gln)

NC_000019.10:g.11113313G>C

CM000681.2:g.11113313G>C

NC_000019.9:g.11223989G>C

CM000681.1:g.11223989G>C

NC_000019.8:g.11084989G>C

NG_009060.1:g.28933G>C

ENST00000558518.6:c.1222G>C

ENST00000252444.9:n.1476G>C

ENST00000455727.6:c.718G>C

ENST00000535915.5:c.1099G>C

ENST00000545707.5:c.841G>C

ENST00000557933.5:c.1222G>C

ENST00000558013.5:c.1222G>C

ENST00000558518.5:c.1222G>C

ENST00000560173.1:n.221G>C

ENST00000560467.1:n.702G>C

NM_000527.4:c.1222G>C

NM_001195798.1:c.1222G>C

NM_001195799.1:c.1099G>C

NM_001195800.1:c.718G>C

NM_001195803.1:c.841G>C

NM_001195798.2:c.1222G>C

NM_001195799.2:c.1099G>C

NM_001195800.2:c.718G>C

NM_001195803.2:c.841G>C

Uncertain Significance

PP3 PM2

PVS1 PS2 PS4 PS3 PS1 BA1 PP1 PP4 PP2 PM6 PM3 PM1 PM4 PM5 BS2 BS4 BS3 BS1 BP5 BP7 BP2 BP3 BP4 BP1

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.1222G>C (p.Glu408Gln) variant is classified as Uncertain significance - insufficient evidence for Familial Hypercholesterolemia by applying evidence codes PM2 and PP3 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 = 0.768. It is above 0.75, so PP3 is met.

PP3

REVEL = 0.768. 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

PVS1

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

PS2

no de novo occurrence

PS4

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

PS3

no functional study performed, so not met

PS1

no other missense variants lead to the same amino acid change in the same codon, so not met

BA1

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

PP1

no segregation data

PP4

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

PP2

not applicable

PM6

no de novo occurrence

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>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 - 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.

BS2

not identified in normolipidemic individuals, so not met

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

BP5

not applicable

BP7

variant is missense, so not met

BP2

no case data

BP3

not applicable

BP4

REVEL = 0.768. It is not below 0.50, so BP4 is not met

BP1

not applicable

Curation History

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.