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]
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  • See Evidence submitted by expert panel for details.

Variant: NM_000527.5(LDLR):c.2531G>A (p.Gly844Asp)

CA023681

3734 (ClinVar)

Gene: LDLR
Condition: hypercholesterolemia, familial
Inheritance Mode: Semidominant inheritance
Link to MONDO
UUID: 58ad8eee-de96-4112-af59-af6615224440

HGVS expressions

NM_000527.5:c.2531G>A
NM_000527.5(LDLR):c.2531G>A (p.Gly844Asp)
NC_000019.10:g.11129654G>A
CM000681.2:g.11129654G>A
NC_000019.9:g.11240330G>A
CM000681.1:g.11240330G>A
NC_000019.8:g.11101330G>A
NG_009060.1:g.45274G>A
ENST00000558518.6:c.2531G>A
ENST00000252444.9:n.2785G>A
ENST00000455727.6:c.2027G>A
ENST00000535915.5:c.2408G>A
ENST00000545707.5:c.1997G>A
ENST00000557933.5:c.2593G>A
ENST00000558013.5:c.2531G>A
ENST00000558518.5:c.2531G>A
ENST00000560628.1:n.108+2000G>A
NM_000527.4:c.2531G>A
NM_001195798.1:c.2531G>A
NM_001195799.1:c.2408G>A
NM_001195800.1:c.2027G>A
NM_001195803.1:c.1997G>A
NM_001195798.2:c.2531G>A
NM_001195799.2:c.2408G>A
NM_001195800.2:c.2027G>A
NM_001195803.2:c.1997G>A

Likely Pathogenic

Met criteria codes 4
PS4 PP4 PP3 PM2
Not Met criteria codes 22
PS2 PS3 PS1 PP1 PP2 PM6 PM3 PM1 PM4 PM5 PVS1 BA1 BS2 BS4 BS3 BS1 BP2 BP3 BP4 BP1 BP5 BP7

Evidence Links 1

Expert Panel

Criteria Specification Information

Criteria Specifications for this VCEP
Evidence submitted by expert panel
Familial Hypercholesterolemia VCEP
NM_000527.5(LDLR):c.2531G>A (p.Gly844Asp) variant is classified as Likely pathogenic for Familial Hypercholesterolemia by applying evidence codes (PS4, PM2, PP3 and PP4) 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: PS4 - Variant meets PM2 and is identified in 14 unrelated index cases fulfilling Simon-Broome criteria published in PMID: 7573037. PM2 - No population data was found for this variant in gnomAD (gnomAD v2.1.1). PP3 - REVEL: 0,939. PP4 - Variant meets PM2 and is identified in 14 unrelated index cases fulfilling Simon-Broome criteria for FH published in PMID: 7573037.
Met criteria codes
PS4
Variant meets PM2 and is identified in 14 unrelated index cases fulfilling Simon-Broome criteria published in PMID: 7573037.
PP4
Variant meets PM2 and is identified in 14 unrelated index cases fulfilling Simon-Broome criteria for FH published in PMID: 7573037.
PP3
REVEL: 0,939. Score is above 0,75.
PM2
No population data was found for this variant in gnomAD (gnomAD v2.1.1).
Not Met criteria codes
PS2
No de novo cases were identified.
PS3
PS3 not met. PMID: 11389828 - defect in polarized targeting of the receptor in hepatocytes.
defect in polarized targeting of the receptor in hepatocytes PubMed:11389828
PS1
No other missense variants leads to the same amino acid change.
PP1
No family members tested.
PP2
Not applicable.
PM6
No de novo cases were identified.
PM3
Not identified in individuals with other variants.
PM1
Missense at codon 844 - it is not exon 4 or any of the 60 Cys residues listed. Not applicable.
PM4
Missense variant. Not applicable.
PM5
One other missense variant in the same codon: (1)NM_000527.4(LDLR):c.2530G>A (p.Gly844Ser) (ClinVar ID 440701) - VUS by these guidelines No other missense variants in the same codon classified as Pathogenic.
PVS1
Missense variant. Not applicable.
BA1
No population data was found for this variant in gnomAD (gnomAD v2.1.1).
BS2
No unaffected individuals identified with the variant.
BS4
No family members tested.
BS3
BS3 not met. PMID: 11389828 - defect in polarized targeting of the receptor in hepatocytes.
defect in polarized targeting of the receptor in hepatocytes PubMed:11389828
BS1
No population data was found for this variant in gnomAD (gnomAD v2.1.1).
BP2
Not identified in individuals with other variants.
BP3
Not applicable.
BP4
REVEL: 0,939. Score is not below 0,50.
BP1
Not applicable.
BP5
Not applicable.
BP7
Missense variant. Not applicable.
Approved on: 2021-06-22
Published on: 2021-06-24
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