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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Variant: NM_000527.5(LDLR):c.1301C>A (p.Thr434Lys)

CA10585392

251773 (ClinVar)

Gene: LDLR
Condition: hypercholesterolemia, familial
Inheritance Mode: Semidominant inheritance
Link to MONDO
UUID: 968c6325-8093-4953-a591-6250a37c3174

HGVS expressions

NM_000527.5:c.1301C>A
NM_000527.5(LDLR):c.1301C>A (p.Thr434Lys)
NC_000019.10:g.11113392C>A
CM000681.2:g.11113392C>A
NC_000019.9:g.11224068C>A
CM000681.1:g.11224068C>A
NC_000019.8:g.11085068C>A
NG_009060.1:g.29012C>A
ENST00000558518.6:c.1301C>A
ENST00000252444.9:n.1555C>A
ENST00000455727.6:c.797C>A
ENST00000535915.5:c.1178C>A
ENST00000545707.5:c.920C>A
ENST00000557933.5:c.1301C>A
ENST00000558013.5:c.1301C>A
ENST00000558518.5:c.1301C>A
ENST00000559340.1:n.22C>A
ENST00000560173.1:n.300C>A
ENST00000560467.1:n.781C>A
NM_000527.4:c.1301C>A
NM_001195798.1:c.1301C>A
NM_001195799.1:c.1178C>A
NM_001195800.1:c.797C>A
NM_001195803.1:c.920C>A
NM_001195798.2:c.1301C>A
NM_001195799.2:c.1178C>A
NM_001195800.2:c.797C>A
NM_001195803.2:c.920C>A

Likely Pathogenic

Met criteria codes 4
PM2 PM5 PS4_Supporting PP4
Not Met criteria codes 18
PM6 PM3 PM1 PM4 PVS1 BS2 BS4 BS3 BS1 BP2 BP3 BP4 PS2 PS3 PS1 PP1 PP3 BA1

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.1301C>A (p.Thr434Lys) variant is classified as Likely Pathogenic for Familial Hypercholesterolemia by applying evidence codes PS4_Supporting, PM2, PM5, and PP4 as defined by the ClinGen Familial Hypercholesterolemia Expert Panel LDLR-specific variant curation guidelines (https://doi.org/10.1016/j.gim.2021.09.012). PS4_Supporting: Variant meets PM2 and is identified in 2 unrelated cases, as follows: 1 case with DLCN >=6 from Service de Biochimie et de Biologie Moléculaire, Hospices Civils de Lyon, Lyon, France; 1 case with clinical criteria based on Defesche J. 2000. Familial hypercholesterolemia. In: Betteridge J (ed): Lipids and Vascular Disease from PMID 11810272. So PS4_Supporting is met. PM2: PopMax MAF = 0.00001 (0.001%) in European (Non-Finnish) exomes+genomes (gnomAD v2.1.1). So, PM2 is met. PM5: 3 other missense variants in the same codon: - NM_000527.5(LDLR):c.1301C>G (p.Thr434Arg) (ClinVar ID 251774) - Pathogenic by these guidelines - NM_000527.5(LDLR):c.1301C>T (p.Thr434Met)(ClinVar ID 251775) - Unknown significance by these guidelines - NM_000527.5(LDLR):c.1300A>C (p.Thr434Pro)(ClinVar ID 496018) - Unknown significance by these guidelines There is 1 variant in the same codon classified as Pathogenic by these guidelines. PP4: Variant meets PM2. Identified in 1 FH case from Service de Biochimie et de Biologie Moléculaire, Hospices Civils de Lyon with clinical DLCN Criteria score ≥ 6, after alternative causes of high cholesterol were excluded.
Met criteria codes
PM2
PopMax MAF = 0.00001 (0.001%) in European (Non-Finnish) exomes+genomes (gnomAD v2.1.1). So, PM2 is met.
PM5
3 other missense variants in the same codon: - NM_000527.5(LDLR):c.1301C>G (p.Thr434Arg) (ClinVar ID 251774) - Pathogenic by these guidelines - NM_000527.5(LDLR):c.1301C>T (p.Thr434Met)(ClinVar ID 251775) - Unknown significance by these guidelines - NM_000527.5(LDLR):c.1300A>C (p.Thr434Pro)(ClinVar ID 496018) - Unknown significance by these guidelines There is 1 variant in the same codon classified as Pathogenic by these guidelines.
PS4_Supporting
Variant meets PM2 and is identified in 2 unrelated cases, as follows: 1 case with DLCN >=6 from Service de Biochimie et de Biologie Moléculaire, Hospices Civils de Lyon, Lyon, France; 1 case with clinical criteria based on Defesche J. 2000. Familial hypercholesterolemia. In: Betteridge J (ed): Lipids and Vascular Disease from PMID 11810272. So PS4_Supporting is met.
PP4
Variant meets PM2. Identified in 1 FH case from Service de Biochimie et de Biologie Moléculaire, Hospices Civils de Lyon with clinical DLCN Criteria score ≥ 6, after alternative causes of high cholesterol were excluded.
Not Met criteria codes
PM6
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
PM3
No data available
PM1
Not in exon 4. Not a cysteine residue.
PM4
No in-frame deletions/insertions
PVS1
Not a null variant.
BS2
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
BS4
No data available
BS3
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
BS1
Allele frequency= 0.00000398.
BP2
No data available
BP3
No in-frame deletions/insertions
BP4
REVEL = 0.652. It is not above 0.75, so splicing evaluation required. Functional data on splicing not available. A) variant not on limits. B) variant is exonic and at least 50bp upstream from the canonical donor site and creates AG. Wild type score= 6.59, Variant score= -0.05; Var/Wt ratio= -0.007. It is below 0.9. C) there is an AG nearby. Variant cryptic score= -16.29, Wild type cryptic score= -10.76; Var criptic/Wt criptic= 1.51, Var criptic/Wt score= -2.47. It is below 0.9. Variant is not predicted to alter splicing.
PS2
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
PS3
PMID 21868016, results: 40% the receptor activity (35% internalization and 40% degradation, 40% binding). Results are below 85% of wild-type activity. However, method and results of original functional data for this variant was not cited.
PS1
No missense variant in the same codon resulting in the same amino acid change.
PP1
No data available
PP3
REVEL = 0.652. It is not above 0.75, so splicing evaluation required. Functional data on splicing not available. A) variant not on limits. B) variant is exonic and at least 50bp upstream from the canonical donor site and creates AG. Wild type score= 6.59, Variant score= -0.05; Var/Wt ratio= -0.007. It is below 0.9. C) there is an AG nearby. Variant cryptic score= -16.29, Wild type cryptic score= -10.76; Var criptic/Wt criptic= 1.51, Var criptic/Wt score= -2.47. It is below 0.9. Variant is not predicted to alter splicing.
BA1
Allele frequency= 0.00000398.
Approved on: 2022-10-28
Published on: 2022-12-24
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