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.1216C>A (p.Arg406=)

CA023436

3746 (ClinVar)

Gene: LDLR
Condition: hypercholesterolemia, familial
Inheritance Mode: Semidominant inheritance
Link to MONDO
UUID: 1bb8fe4b-fd4a-4ab2-952f-71ea0f6664c5

HGVS expressions

NM_000527.5:c.1216C>A
NM_000527.5(LDLR):c.1216C>A (p.Arg406=)
ENST00000558518.6:c.1216C>A
ENST00000252444.9:n.1470C>A
ENST00000455727.6:c.712C>A
ENST00000535915.5:c.1093C>A
ENST00000545707.5:c.835C>A
ENST00000557933.5:c.1216C>A
ENST00000558013.5:c.1216C>A
ENST00000558518.5:c.1216C>A
ENST00000560173.1:n.215C>A
ENST00000560467.1:n.696C>A
NM_000527.4:c.1216C>A
NM_001195798.1:c.1216C>A
NM_001195799.1:c.1093C>A
NM_001195800.1:c.712C>A
NM_001195803.1:c.835C>A
NM_001195798.2:c.1216C>A
NM_001195799.2:c.1093C>A
NM_001195800.2:c.712C>A
NM_001195803.2:c.835C>A
NC_000019.10:g.11113307C>A
CM000681.2:g.11113307C>A
NC_000019.9:g.11223983C>A
CM000681.1:g.11223983C>A
NC_000019.8:g.11084983C>A
NG_009060.1:g.28927C>A

Likely Pathogenic

Met criteria codes 5
PS4_Supporting PM3 PM2 PS3_Moderate PP4
Not Met criteria codes 21
PM1 PM4 PM5 PM6 PVS1 BA1 BS2 BS4 BS3 BS1 BP5 BP7 BP2 BP3 BP4 BP1 PS2 PS1 PP1 PP3 PP2

Evidence Links 0

Expert Panel

Criteria Specification Information

Criteria Specifications for this VCEP
Evidence submitted by expert panel
Familial Hypercholesterolemia VCEP
The NM_000527.5(LDLR):c.1216C>A (p.Arg406=) variant is classified as Likely pathogenic for Familial Hypercholesterolemia by applying evidence codes (PM2, PM3, PS3_Moderate, 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 = 0.00005441 (0.005%) in East Asian exomes (gnomAD v2.1.1). PM3 - Variant meets PM2 and is identified in one compound heterozygote with a homozygous FH phenotype published in PMID 28028493 (Patient F3 compound with NM_000527.5(LDLR):c.760C>T (p.Gln254Ter) (ClinVar ID 251436), LDLc: 18.21 mmol/l). Additional variant classified as Pathogenic by these guidelines. PS3_moderate - Level 2 FS: PMID: 19371225 - Htz patient's Epstein-Barr virus transformed lymphocytes. RNA assays. Mutant mRNA 25%-45% of total amount. PP4 - Variant meets PM2. Variant identified in 2 index cases. PS4_supporting - Variant meets PM2. Variant identified in 2 index cases.
Met criteria codes
PS4_Supporting
Variant meets PM2. Variant identified in 2 index cases (1 case from Cardiovascular Genetics Laboratory (PathWest Laboratory Medicine WA) with DLCN criteria; 1 case in PMID 28028493 (EAS FH criteria used)).
PM3
Variant meets PM2 and is identified in one compound heterozygote with a homozygous FH phenotype published in PMID 28028493 (Patient F3 compound with NM_000527.5(LDLR):c.760C>T (p.Gln254Ter) (ClinVar ID 251436), LDLc: 18.21 mmol/l). Additional variant classified as Pathogenic by these guidelines
PM2
PopMax MAF = 0.00005441 (0.005%) in East Asian exomes (gnomAD v2.1.1). MAF is under 0.02%.
PS3_Moderate
Level 2 FS: PMID: 19371225 - Htz patient's Epstein-Barr virus transformed lymphocytes. RNA assays. Mutant mRNA 25%-45% of total amount. Level 3 FS: PMID: 17335829 - Htz patient's Epstein-Barr virus transformed lymphocytes, RNA assays - skipping of 31nts from exon 9 (p.Ser397Thrfs*6).
PP4
Variant meets PM2. Variant identified in 2 index cases (1 case from Cardiovascular Genetics Laboratory (PathWest Laboratory Medicine WA) with DLCN criteria; 1 case in PMID 28028493 (EAS FH criteria used)).
Not Met criteria codes
PM1
Synonymous variant. Not applicable.
PM4
Not applicable.
PM5
Synonymous variant. Not applicable.
PM6
No de novo cases were identified.
PVS1
Synonymous variant. Not applicable.
BA1
no FAF, just total MAF = 0.000003983 (0.0004%) in East Asian exomes (gnomAD v2.1.1). MAF is not above 0.5%.
BS2
No unaffected individuals identified with the variant.
BS4
No family members tested.
BS3
Level 3 FS: PMID: 19371225 - Htz patient's Epstein-Barr virus transformed lymphocytes. RNA assays. Mutant mRNA 25%-45% of total amount. Level 3 FS: PMID: 17335829 - Htz patient's Epstein-Barr virus transformed lymphocytes, RNA assays - skipping of 31nts from exon 9 (p.Ser397Thrfs*6).
BS1
no FAF, just total MAF = 0.000003983 (0.0004%) in East Asian exomes (gnomAD v2.1.1). MAF is not above 0.2%.
BP5
Not applicable.
BP7
MES ratio: 7.59016393442623. MES is > 0,8.
BP2
Not applicable.
BP3
Not applicable.
BP4
Functional splicing data available. Not applicable.
BP1
Not applicable.
PS2
No de novo cases were identified.
PS1
Synonymous variant. Not applicable.
PP1
No family members tested.
PP3
Functional splicing data available. Not applicable.
PP2
Not applicable.
Approved on: 2021-06-08
Published on: 2021-06-24
The information on this website is not intended for direct diagnostic use or medical decision-making without review by a genetics professional. Individuals should not change their health behavior solely on the basis of information contained on this website. If you have questions about the information contained on this website, please see a health care professional.
¤ Powered by BCM's Genboree.