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.1024G>T (p.Asp342Tyr)

CA10585255

251603 (ClinVar)

Gene: LDLR
Condition: hypercholesterolemia, familial
Inheritance Mode: Semidominant inheritance
Link to MONDO
UUID: da53a4b8-8d4a-48ca-a7d0-3af4324c21b0

HGVS expressions

NM_000527.5:c.1024G>T
NM_000527.5(LDLR):c.1024G>T (p.Asp342Tyr)
ENST00000558518.6:c.1024G>T
ENST00000252444.9:n.1278G>T
ENST00000455727.6:c.520G>T
ENST00000535915.5:c.901G>T
ENST00000545707.5:c.643G>T
ENST00000557933.5:c.1024G>T
ENST00000558013.5:c.1024G>T
ENST00000558518.5:c.1024G>T
ENST00000560173.1:n.23G>T
ENST00000560467.1:n.541-779G>T
NM_000527.4:c.1024G>T
NM_001195798.1:c.1024G>T
NM_001195799.1:c.901G>T
NM_001195800.1:c.520G>T
NM_001195803.1:c.643G>T
NM_001195798.2:c.1024G>T
NM_001195799.2:c.901G>T
NM_001195800.2:c.520G>T
NM_001195803.2:c.643G>T
NC_000019.10:g.11110735G>T
CM000681.2:g.11110735G>T
NC_000019.9:g.11221411G>T
CM000681.1:g.11221411G>T
NC_000019.8:g.11082411G>T
NG_009060.1:g.26355G>T

Uncertain Significance

Met criteria codes 3
PP4 PM2 PS4_Supporting
Not Met criteria codes 23
PS2 PS1 PS3 BP4 BP1 BP2 BP3 BP7 BP5 BA1 PP3 PP2 PP1 PM3 PM4 PM1 PM5 PM6 PVS1 BS2 BS4 BS3 BS1

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.1024G>T (p.Asp342Tyr) variant is classified as Uncertain significance - insufficient evidence for Familial Hypercholesterolemia by applying evidence codes (PM2, PP4 and PS4_Supporting) as defined by the ClinGen Familial Hypercholesterolemia Expert Panel LDLR-specific variant curation guidelines (citation pending). The supporting evidence is as follows: PM2 - Not found in gnomAD (accessed 5th June 2020). FAF is under 0.02%, so PM2 is Met; PP4 - Variant meets PM2. Identified in 1 FH case from Center of molecular biology and gene therapy who fulfills Simon-Broome criteria (high LDL value, family history of CVD = possible FH). ---- PP4 is Met; PS4_supporting - Variant meets PM2. Variant identified in 2 index cases from Center of molecular biology and gene therapy with Simon-Broome criteria for FH. ---- PS4_Supporting is Met.
Met criteria codes
PP4
Variant meets PM2. Identified in 1 FH case from Center of molecular biology and gene therapy who fulfills Simon-Broome criteria (high LDL value, family history of CVD = possible FH). ---- PP4 is Met
PM2
Not found in gnomAD (accessed 5th June 2020). FAF is under 0.02%, so PM2 is Met.
PS4_Supporting
Variant meets PM2. Variant identified in 2 index cases from Center of molecular biology and gene therapy with Simon-Broome criteria for FH. ---- PS4_Supporting is Met
Not Met criteria codes
PS2
no de novo cases were identified, so PS2 is Not Met
PS1
No variant described that leads to the same amino acid change, so PS1 is Not Met
PS3
no functional assays performed, not applicable
BP4
REVEL = 0.563. It is not below 0.15, BP4 is Not Met
BP1
Not applicable
BP2
not identified in individuals with other variants, so BP2 is Not Met
BP3
Not applicable
BP7
Missense variant, so BP7 is not applicable
BP5
Not applicable
BA1
Not found in gnomAD (accessed 5th June 2020). FAF is not above 0.5%, so BA1 is Not Met.
PP3
REVEL = 0.563. It is not above 0.75, splicing needed. Functional data on splicing not available. A) variant not on limits. B) variant is exonic and at least 50bp downstream from canonical acceptor site, but it does not create GT. C) there is no GT nearby. No splicing prediction is applicable, so PP3 is Not Met
PP2
Not applicable
PP1
no family members were tested, so PP1 is Not Met
PM3
not identified in individuals with other variants, so PM3 is Not Met
PM4
Missense variant, not applicable
PM1
Missense at codon 342. PM2 is Met, but it is not exon 4 or any of the 60 Cys residues listed, so PM1 is Not Met
PM5
Two more missense variants described in same codon: (1)NM_000527.5(LDLR):c.1024G>A (p.Asp342Asn) (ClinVar ID 161274) with Conflicting interpretations of pathogenicity​ - Benign(2);Likely benign(3);Uncertain significance(4) - by multiple submitters (Accession: SCV000190294.2, Submitted: (Nov 22, 2015); Accession: SCV000295146.2, Submitted: (Apr 20, 2016); Accession: SCV000503281.1, Submitted: (Jan 23, 2017); Accession: SCV000588540.1, Submitted: (Aug 04, 2017); Accession: SCV000234648.10, Submitted: (Jan 29, 2019); Accession: SCV000903570.1, Submitted: (Nov 06, 2018); Accession: SCV000271916.3, Submitted: (Mar 21, 2019); Accession: SCV000627010.4, Submitted: (Jan 29, 2020); Accession: SCV001285933.1, Submitted: (Feb 20, 2020)) - 1 star status (2)NM_000527.5(LDLR):c.1026C>G (p.Asp342Glu) (ClinVar ID 251604) with Conflicting interpretations of pathogenicity​ - Likely benign(2);Uncertain significance(3) - by multiple submitters (Accession: SCV000295148.2, Submitted: (Apr 20, 2016); Accession: SCV000503282.1, Submitted: (Jan 23, 2017); Accession: SCV000697180.1, Submitted: (Jan 25, 2018); Accession: SCV000520996.4, Submitted: (Jan 29, 2019); Accession: SCV001229705.1, Submitted: (Feb 06, 2020)) - 1 star status --- no variants classified as P, none have a 3-star status (not done by FH VCEP), so PM5 is Not Met
PM6
no de novo cases were identified, so PM6 is Not Met
PVS1
Missense variant, PVS1 Not Met
BS2
no unaffected individuals identified with the variant, so BS2 is Not Met
BS4
no family members were tested, so BS4 is Not Met
BS3
no functional assays performed, not applicable
BS1
Not found in gnomAD (accessed 5th June 2020). FAF is not above 0.2%, so BS1 is Not Met.
Approved on: 2020-08-11
Published on: 2021-06-24
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