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
  • See Evidence submitted by expert panel for details.

Variant: NM_000527.5(LDLR):c.1217G>A (p.Arg406Gln)

CA033088

228798 (ClinVar)

Gene: LDLR
Condition: hypercholesterolemia, familial
Inheritance Mode: Semidominant inheritance
Link to MONDO
UUID: 85b170dc-d751-4e93-90df-66867783e4f0

HGVS expressions

NM_000527.5:c.1217G>A
NM_000527.5(LDLR):c.1217G>A (p.Arg406Gln)
ENST00000558518.6:c.1217G>A
ENST00000252444.9:n.1471G>A
ENST00000455727.6:c.713G>A
ENST00000535915.5:c.1094G>A
ENST00000545707.5:c.836G>A
ENST00000557933.5:c.1217G>A
ENST00000558013.5:c.1217G>A
ENST00000558518.5:c.1217G>A
ENST00000560173.1:n.216G>A
ENST00000560467.1:n.697G>A
NM_000527.4:c.1217G>A
NM_001195798.1:c.1217G>A
NM_001195799.1:c.1094G>A
NM_001195800.1:c.713G>A
NM_001195803.1:c.836G>A
NM_001195798.2:c.1217G>A
NM_001195799.2:c.1094G>A
NM_001195800.2:c.713G>A
NM_001195803.2:c.836G>A
NC_000019.10:g.11113308G>A
CM000681.2:g.11113308G>A
NC_000019.9:g.11223984G>A
CM000681.1:g.11223984G>A
NC_000019.8:g.11084984G>A
NG_009060.1:g.28928G>A

Likely Pathogenic

Met criteria codes 5
PP4 PP3 PM2 PM5 PS4_Supporting
Not Met criteria codes 21
PS2 PS3 PS1 PP1 PP2 PM6 PM3 PM1 PM4 BA1 BS2 PVS1 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.1217G>A (p.Arg406Gln) variant is classified as Likely pathogenic for Familial Hypercholesterolemia by applying evidence codes (PM2, PM5, PP3, PP4, PS4_Supporting) 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 = 0.00006164 (0.006%) in African/African American (gnomAD v2.1.1). PM5 - Two other missense variants described in the same codon (accessed 19 August 2020): --- 1 variant classified as Pathogenic by these guidelines. PP3 - REVEL: 0,809. PP4 - Variant meets PM2. Variant identified in 2 index cases fulfilling Simon-Broome criteria. PS4_supporting - Variant meets PM2. Variant identified in 2 index cases (PMID: 10882754 - 1 case with Simon-Broome criteria; PMID: 17094996 - 1 case with Simon-Broome criteria).
Met criteria codes
PP4
Variant meets PM2. Variant identified in 2 index cases fulfilling Simon-Broome criteria (PMID: 10882754; PMID: 17094996).
PP3
REVEL: 0,809. Score is above 0,75.
PM2
PopMax MAF = 0.00006164 (0.006%) in African/African American (gnomAD v2.1.1). MAF is below 0.02%.
PM5
Two other missense variants described in the same codon (accessed 19 August 2020): (1)NM_000527.5(LDLR):c.1216C>T (p.Arg406Trp) (ClinVar ID226351) - classified as Pathogenic by these guidelines. (2)NM_000527.5(LDLR):c.1217G>C (p.Arg406Pro) (ClinVar ID 226352) - classified as Likely pathogenic by these guidelines. --- 1 variant classified as Pathogenic by these guidelines, so PM5 is met
PS4_Supporting
Variant meets PM2. Variant identified in 2 index cases (PMID: 10882754 - 1 case with Simon-Broome criteria; PMID: 17094996 - 1 case with Simon-Broome criteria).
Not Met criteria codes
PS2
No de novo cases were identified.
PS3
No functional assays performed/found - not applicable.
PS1
No variant described that 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 406. PM2 is Met, but it is not exon 4 or any of the 60 Cys residues listed. Not applicable.
PM4
Missense variant. Not applicable.
BA1
no FAF, just total MAF = 0.00001593 (0.0016%) in African/African American (gnomAD v2.1.1). MAF is not above 0.5%
BS2
No unaffected individuals identified with the variant.
PVS1
Missense variant. Not applicable.
BS4
No family members tested.
BS3
No functional assays performed/found - not applicable.
BS1
no FAF, just total MAF = 0.00001593 (0.0016%) in African/African American (gnomAD v2.1.1). MAF 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: 0,809. Score is not below 0,15.
BP1
Not applicable.
Approved on: 2021-06-09
Published on: 2021-06-24
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