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

CA10585401

251784 (ClinVar)

Gene: LDLR

Condition: hypercholesterolemia, familial

Inheritance Mode: Semidominant inheritance

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

Approved on: 2022-01-17

Published on: 2022-07-12

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

• Met criteria codes: PM5 PM2 PP3

• Not Met criteria codes: BA1 PM3 PM1 PM4 PM6 BS4 BS3 BS1 BP2 BP4 BP7 PVS1 PS2 PS4 PS3 PS1 PP4 PP1

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

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.

Met criteria codes

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

Not Met criteria codes

• BA1: No population data was found for this variant in gnomAD (gnomAD v2.1.1), so BA1 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.
• 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.
• BP7: Variant is not synonymous, so BP7 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.
• 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.
• 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.