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.1323C>G (p.Ile441Met)

CA10585401

251784 (ClinVar)

Gene: LDLR

Condition: hypercholesterolemia, familial

Inheritance Mode: Semidominant inheritance

Link to MONDO

UUID: e2c545fd-bde0-4a3b-98d9-d3ced9f509bf

HGVS expressions

NM_000527.5:c.1323C>G

NM_000527.5(LDLR):c.1323C>G (p.Ile441Met)

NC_000019.10:g.11113414C>G

CM000681.2:g.11113414C>G

NC_000019.9:g.11224090C>G

CM000681.1:g.11224090C>G

NC_000019.8:g.11085090C>G

NG_009060.1:g.29034C>G

ENST00000558518.6:c.1323C>G

ENST00000252444.9:n.1577C>G

ENST00000455727.6:c.819C>G

ENST00000535915.5:c.1200C>G

ENST00000545707.5:c.942C>G

ENST00000557933.5:c.1323C>G

ENST00000558013.5:c.1323C>G

ENST00000558518.5:c.1323C>G

ENST00000559340.1:n.44C>G

ENST00000560173.1:n.322C>G

ENST00000560467.1:n.803C>G

NM_000527.4:c.1323C>G

NM_001195798.1:c.1323C>G

NM_001195799.1:c.1200C>G

NM_001195800.1:c.819C>G

NM_001195803.1:c.942C>G

NM_001195798.2:c.1323C>G

NM_001195799.2:c.1200C>G

NM_001195800.2:c.819C>G

NM_001195803.2:c.942C>G

Uncertain Significance

PP3 PM5 PM2

BP7 BP2 BP4 PS2 PS4 PS3 PS1 PVS1 BA1 PP4 PP1 PM3 PM1 PM4 PM6 BS4 BS3 BS1

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.1323C>G (p.Ile441Met) variant is classified as Uncertain significance - insufficient evidence for Familial Hypercholesterolemia by applying evidence codes (PM2, PP3 and PM5) 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 is absent from gnomAD (gnomAD v2.1.1), so PM2 is Met. PP3 - REVEL = 0.769. It is above 0.75, so PP3 is Met. PM5 - 2 other missense variants in the same codon: - NM_000527.5(LDLR):c.1322T>C (p.Ile441Thr) (ClinVar ID: 251783) - Pathogenic by these guidelines - NM_000527.5(LDLR):c.1322T>A (p.Ile441Asn) (ClinVar ID: 251782) - VUS by these guidelines There is 1 variant in the same codon classified as Pathogenic by these guidelines, so PM5 is Met.

PP3

REVEL = 0.769. It is above 0.75, so PP3 is Met.

PM5

2 other missense variants in the same codon: - NM_000527.5(LDLR):c.1322T>C (p.Ile441Thr) (ClinVar ID: 251783) - Pathogenic by these guidelines - NM_000527.5(LDLR):c.1322T>A (p.Ile441Asn) (ClinVar ID: 251782) - VUS by these guidelines There is 1 variant in the same codon classified as Pathogenic by these guidelines, so PM5 is Met.

PM2

This variant is absent from gnomAD (gnomAD v2.1.1), so PM2 is Met.

BP7

Variant is not synonymous, so BP7 is Not Met.

BP2

Not observed in trans with other LP/P variants, so BP2 is Not Met.

BP4

REVEL = 0.769. It is not below 0.50, so BP4 is Not Met.

PS2

de novo occurrence data not reported, so PS2 is Not Met.

PS4

Variant meets PM2, but data reported does not meet any validated criteria, so PS4 is Not Met.

PS3

Functional studies are performed in compound heterozygous patients cells, so PS3 is not applicable.

PS1

No more missense variants that lead to the same amino acid change, so PS1 is Not Met.

PVS1

Variant is missense, so PVS1 is Not Met

BA1

No population data was found for this variant in gnomAD (gnomAD v2.1.1), so BA1 is Not Met.

PP4

Variant meets PM2, but data reported does not meet any validated criteria, so PS4 is Not Met.

PP1

Segregation data not reported, so PP1 is Not Met.

PM3

Not observed in trans with other LP/P variants, so PM3 is Not Met.

PM1

Variant meets PM2 but is not located in exon 4 or alters a cysteine residues, so PM1 is Not Met.

PM4

Variant meets PM2 and is missense, so PM4 is Not Met.

PM6

de novo occurrence data not reported, so PM6 is Not Met.

BS4

Lack of segregation data not reported, so BS4 is Not Met.

BS3

Functional studies are performed in compound heterozygous patients cells, so BS3 is not applicable.

BS1

No population data was found for this variant in gnomAD (gnomAD v2.1.1), so BS1 is Not Met.

Approved on: 2022-01-17

Published on: 2022-07-12

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