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]
Link to SEPIO compliant JSON-LD document

Variant: NM_000527.5(LDLR):c.1070A>G (p.Glu357Gly)

CA031903

251651 (ClinVar)

Gene: LDLR
Condition: hypercholesterolemia, familial
Inheritance Mode: Semidominant inheritance
Link to MONDO
UUID: 83b4122f-0893-4af8-b56c-84932e1db318

HGVS expressions

NM_000527.5:c.1070A>G
NM_000527.5(LDLR):c.1070A>G (p.Glu357Gly)
NC_000019.10:g.11111523A>G
CM000681.2:g.11111523A>G
NC_000019.9:g.11222199A>G
CM000681.1:g.11222199A>G
NC_000019.8:g.11083199A>G
NG_009060.1:g.27143A>G
ENST00000558518.6:c.1070A>G
ENST00000252444.9:n.1324A>G
ENST00000455727.6:c.566A>G
ENST00000535915.5:c.947A>G
ENST00000545707.5:c.689A>G
ENST00000557933.5:c.1070A>G
ENST00000558013.5:c.1070A>G
ENST00000558518.5:c.1070A>G
ENST00000560173.1:n.69A>G
ENST00000560467.1:n.550A>G
NM_000527.4:c.1070A>G
NM_001195798.1:c.1070A>G
NM_001195799.1:c.947A>G
NM_001195800.1:c.566A>G
NM_001195803.1:c.689A>G
NM_001195798.2:c.1070A>G
NM_001195799.2:c.947A>G
NM_001195800.2:c.566A>G
NM_001195803.2:c.689A>G

Uncertain Significance

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

Evidence Links 0

Expert Panel

Criteria Specification Information

Criteria Specification: ClinGen Familial Hypercholesterolemia Expert Panel Specifications to the ACMG/AMP Variant Classification Guidelines Version 1.2

Criteria Specification Approval History
Criteria Specifications for this VCEP
Evidence submitted by expert panel
Familial Hypercholesterolemia VCEP
The NM_000527.5(LDLR):c.1070A>G (p.Glu357Gly) variant is classified as Uncertain significance - insufficient evidence for Familial Hypercholesterolemia by applying evidence codes (PM2, PP3, PP4 and PS4-supporting) 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 - PopMax MAF = 0.000008800 (0.00088%) in European (Non-Finnish) exomes+genomes (gnomAD v2.1.1). PP3 - REVEL = 0.984. PP4 - Variant meets PM2 and is identified in at least one case who fufills clinical criteria for FH (see PS4 for details), after alternative causes of high cholesterol were excluded. PS4_supporting - Variant meets PM2 and is identified in 4 index cases (3 cases with Simon-Broome criteria of possible FH in PMID: 34456049 (Marco-Benedí et al., 2022), Spain; 1 case with internationally accepted criteria (Defesche et al, 2000) in PMID: 16250003 (Fouchier et al, 2005), The Netherlands.
Met criteria codes
PP4
Variant meets PM2 and is identified in at least one case who fufills clinical criteria for FH (see PS4 for details), after alternative causes of high cholesterol were excluded.
PP3
REVEL = 0.984
PM2
PopMax MAF = 0.000008800 (0.00088%) in European (Non-Finnish) exomes+genomes (gnomAD v2.1.1)
PS4_Supporting
Variant meets PM2 and is identified in 4 index cases (3 cases with Simon-Broome criteria of possible FH in PMID: 34456049 (Marco-Benedí et al., 2022), Spain; 1 case with internationally accepted criteria (Defesche et al, 2000) in PMID: 16250003 (Fouchier et al, 2005), The Netherlands.
Not Met criteria codes
BA1
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
PVS1
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
BS2
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
BS4
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
BS3
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
BS1
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
BP2
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
BP3
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
BP4
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
BP1
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
BP5
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
BP7
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
PS2
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
PS3
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
PS1
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
PP1
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
PP2
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
PM3
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
PM1
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
PM4
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
PM5
2 other missense variants in the same codon: - NM_000527.5(LDLR):c.1069G>A (p.Glu357Lys) (ClinVar ID 251649) - Likely pathogenic by these guidelines - NM_000527.5(LDLR):c.1069G>C (p.Glu357Gln) (ClinVar ID 431519) - Uncertain significance by these guidelines There is no variant in the same codon classified as Pathogenic by these guidelines.
PM6
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
Approved on: 2023-04-28
Published on: 2023-04-30
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