Evidence Repository
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.1322T>A (p.Ile441Asn)

CA10585399

251782 (ClinVar)

Gene: LDLR
Condition: hypercholesterolemia, familial
Inheritance Mode: Semidominant inheritance
Link to MONDO
UUID: 881c0ba5-93a1-4a86-86c9-645cd2e9c314
Approved on: 2022-01-17
Published on: 2022-07-12

HGVS expressions

NM_000527.5:c.1322T>A
NM_000527.5(LDLR):c.1322T>A (p.Ile441Asn)
NC_000019.10:g.11113413T>A
CM000681.2:g.11113413T>A
NC_000019.9:g.11224089T>A
CM000681.1:g.11224089T>A
NC_000019.8:g.11085089T>A
NG_009060.1:g.29033T>A
ENST00000558518.6:c.1322T>A
ENST00000252444.9:n.1576T>A
ENST00000455727.6:c.818T>A
ENST00000535915.5:c.1199T>A
ENST00000545707.5:c.941T>A
ENST00000557933.5:c.1322T>A
ENST00000558013.5:c.1322T>A
ENST00000558518.5:c.1322T>A
ENST00000559340.1:n.43T>A
ENST00000560173.1:n.321T>A
ENST00000560467.1:n.802T>A
NM_000527.4:c.1322T>A
NM_001195798.1:c.1322T>A
NM_001195799.1:c.1199T>A
NM_001195800.1:c.818T>A
NM_001195803.1:c.941T>A
NM_001195798.2:c.1322T>A
NM_001195799.2:c.1199T>A
NM_001195800.2:c.818T>A
NM_001195803.2:c.941T>A
More

Uncertain Significance

Met criteria codes 3
PP3 PM2 PM5
Not Met criteria codes 17
BS4 BS1 BS2 BP7 BP2 BP4 PVS1 PS2 PS4 PS1 BA1 PP1 PP4 PM6 PM3 PM1 PM4

Evidence Links 0

Expert Panel

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.1322T>A (p.Ile441Asn) 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 = 0.859. 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.1323C>G (p.Ile441Met) (ClinVar ID: 251784) - VUS by these guidelines There is 1 variant in the same codon classified as Pathogenic by these guidelines, so PM5 is Met.
Met criteria codes
PP3
REVEL = 0.859. It is above 0.75, so PP3 is Met.
PM2
This variant is absent from gnomAD (gnomAD v2.1.1), so PM2 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.1323C>G (p.Ile441Met) (ClinVar ID: 251784) - VUS by these guidelines There is 1 variant in the same codon classified as Pathogenic by these guidelines, so PM5 is Met.
Not Met criteria codes
BS4
Lack of segregation data not reported, so BS4 is Not Met.
BS1
No population data was found for this variant in gnomAD (gnomAD v2.1.1), so BS1 is Not Met.
BS2
Case-control data not reported, so BS2 is Not 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 = 0.859. It is not below 0.50, so BP4 is Not Met.
PVS1
Variant is missense, so PVS1 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.
PS1
No more missense variants that lead to the same amino acid change, so PS1 is Not Met.
BA1
No population data was found for this variant in gnomAD (gnomAD v2.1.1), so BA1 is Not Met.
PP1
Segregation data not reported, so PP1 is Not Met.
PP4
Variant meets PM2, but data reported does not meet any validated criteria, so PP4 is Not Met.
PM6
de novo occurrence data not reported, so PM6 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.
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.
¤ Powered by BCM's Genboree.