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.1576C>T (p.Pro526Ser)

CA023533

183120 (ClinVar)

Gene: LDLR
Condition: hypercholesterolemia, familial
Inheritance Mode: Semidominant inheritance
Link to MONDO
UUID: fd1d2de9-2acd-4e4a-820d-02e74d6b59b6

HGVS expressions

NM_000527.5:c.1576C>T
NM_000527.5(LDLR):c.1576C>T (p.Pro526Ser)
ENST00000558518.6:c.1576C>T
ENST00000252444.9:n.1830C>T
ENST00000455727.6:c.1072C>T
ENST00000535915.5:c.1453C>T
ENST00000545707.5:c.1195C>T
ENST00000557933.5:c.1576C>T
ENST00000558013.5:c.1576C>T
ENST00000558518.5:c.1576C>T
ENST00000559340.1:n.297C>T
NM_000527.4:c.1576C>T
NM_001195798.1:c.1576C>T
NM_001195799.1:c.1453C>T
NM_001195800.1:c.1072C>T
NM_001195803.1:c.1195C>T
NM_001195798.2:c.1576C>T
NM_001195799.2:c.1453C>T
NM_001195800.2:c.1072C>T
NM_001195803.2:c.1195C>T
NC_000019.10:g.11113752C>T
CM000681.2:g.11113752C>T
NC_000019.9:g.11224428C>T
CM000681.1:g.11224428C>T
NC_000019.8:g.11085428C>T
NG_009060.1:g.29372C>T

Uncertain Significance

Met criteria codes 4
PS4_Supporting PP4 PP3 PM2
Not Met criteria codes 22
PS2 PS3 PS1 PP1 PP2 PM6 PM3 PM1 PM4 PM5 PVS1 BA1 BS2 BS4 BS3 BS1 BP5 BP7 BP2 BP3 BP4 BP1

Evidence Links 0

Expert Panel

Criteria Specification Information

Criteria Specifications for this VCEP
Evidence submitted by expert panel
Familial Hypercholesterolemia VCEP
NM_000527.5(LDLR):c.1576C>T (p.Pro526Ser) variant is classified as variant of Uncertain significance for Familial Hypercholesterolemia by applying evidence codes (PM2, PP3, PP4 and PS4_Supportive) 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 - PopMax MAF = 0.00002326 (0.002%) in European-non Finnish exomes (gnomAD v2.1.1). PP3 - REVEL: 0,952. PP4 - Variant meets PM2. Variant identified in 5 index cases (1 case from Color laboratory with Simon-Broome criteria; 1 case from GeneDx laboratory with Simon Broome criteria; 1 cases from University of British Columbia with DLCN criteria; 2 cases fulfilling Simeon-Broome criteria published in PMID: 9259195). PS4_supporting - Variant meets PM2. Variant identified in 5 index cases.
Met criteria codes
PS4_Supporting
Variant meets PM2. Variant identified in 5 index cases (1 case from Color laboratory with Simon-Broome criteria; 1 case from GeneDx laboratory with Simon Broome criteria; 1 cases from University of British Columbia with DLCN criteria; 2 cases fulfilling Simeon-Broome criteria published in PMID: 9259195).
PP4
Variant meets PM2. Variant identified in 5 index cases (1 case from Color laboratory with Simon-Broome criteria; 1 case from GeneDx laboratory with Simon Broome criteria; 1 cases from University of British Columbia with DLCN criteria; 2 cases fulfilling Simeon-Broome criteria published in PMID: 9259195).
PP3
REVEL: 0,952. Score is above 0,75.
PM2
PopMax MAF = 0.00002326 (0.002%) in European-non Finnish exomes (gnomAD v2.1.1). MAF is below 0.02%.
Not Met criteria codes
PS2
No de novo cases were identified.
PS3
PMID: 1301956 - Htz with unknown. Not applicable.
PS1
No variant described that leads to the same amino acid change.
PP1
No family members tested. Not applicable.
PP2
Not applicable.
PM6
No de novo cases were identified.
PM3
Not identified in individuals with other variants.
PM1
Missense at codon 526. PM2 is Met, but it is not exon 4 or any of the 60 Cys residues listed. Not applicable.
PM4
Missense variant. Not applicable.
PM5
No other missense variants classified as Pathogenic in the same codon. Four missense variants described in the same codon (accessed 19 August 2020): (1)NM_000527.5(LDLR):c.1576C>A (p.Pro526Thr) (ClinVar ID 251903) - classified as VUS by these guidelines; (2)NM_000527.4(LDLR):c.1577C>A (p.Pro526His) (ClinVar ID 496019) - classified as VUS by these guidelines; (3)NM_000527.4(LDLR):c.1577C>T (p.Pro526Leu) (ClinVar ID 431531) - classified as VUS by these guidelines; (4)NM_000527.5(LDLR):c.1577C>G (p.Pro526Arg) (ClinVar ID 251904) - classified as VUS by these guidelines.
PVS1
Missense variant. Not applicable.
BA1
FAF = 0.000002920 (0.0002920%) in European-non Finnish exomes (gnomAD v2.1.1). FAF is not above 0.5%
BS2
No unaffected individuals identified with the variant.
BS4
No family members tested. Not applicable.
BS3
PMID: 1301956 - Htz with unknown. Not applicable.
BS1
FAF = 0.000002920 (0.0002920%) in European-non Finnish exomes (gnomAD v2.1.1). FAF is not above 0.2%
BP5
Not applicable.
BP7
Missense variant. Not applicable.
BP2
Not identified in individuals with other variants.
BP3
Not applicable.
BP4
REVEL: 0.952. Score is not below 0,15.
BP1
Not applicable.
Approved on: 2021-06-09
Published on: 2021-06-24
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