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]
  • Gene obtained from curated document aligns with the Allele Registry but not with ClinVar data

Variant: NM_000527.5(LDLR):c.979C>T (p.His327Tyr)

CA030996

251583 (ClinVar)

Gene: LDLR
Condition: hypercholesterolemia, familial
Inheritance Mode: Semidominant inheritance
Link to MONDO
UUID: 1f1cd05c-e5a0-47d6-875e-1f9b4bd69505
Approved on: 2022-07-22
Published on: 2025-03-07

HGVS expressions

NM_000527.5:c.979C>T
NM_000527.5(LDLR):c.979C>T (p.His327Tyr)
NC_000019.10:g.11110690C>T
CM000681.2:g.11110690C>T
NC_000019.9:g.11221366C>T
CM000681.1:g.11221366C>T
NC_000019.8:g.11082366C>T
NG_009060.1:g.26310C>T
ENST00000252444.10:c.1237C>T
ENST00000559340.2:c.979C>T
ENST00000560467.2:c.941-824C>T
ENST00000558518.6:c.979C>T
ENST00000252444.9:c.1233C>T
ENST00000455727.6:c.475C>T
ENST00000535915.5:c.856C>T
ENST00000545707.5:c.598C>T
ENST00000557933.5:c.979C>T
ENST00000558013.5:c.979C>T
ENST00000558518.5:c.979C>T
ENST00000560467.1:c.541-824C>T
NM_000527.4:c.979C>T
NM_001195798.1:c.979C>T
NM_001195799.1:c.856C>T
NM_001195800.1:c.475C>T
NM_001195803.1:c.598C>T
NM_001195798.2:c.979C>T
NM_001195799.2:c.856C>T
NM_001195800.2:c.475C>T
NM_001195803.2:c.598C>T
More

Uncertain Significance

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

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

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Criteria Specification Approval History
Criteria Specifications for this VCEP
Evidence submitted by expert panel
Familial Hypercholesterolemia VCEP
NM_000527.5(LDLR):c.979C>T (p.His327Tyr) variant is classified as Uncertain significance - insufficient evidence for Familial Hypercholesterolemia by applying ACMG/AMP evidence codes PM2, PP3, PP4 and PS4_Supporting as defined by the ClinGen Familial Hypercholesterolemia Expert Panel LDLR-specific variant curation guidelines (specification version 1.2) on 22 July 2022. The supporting evidence is as follows: PM2 - Variant is found in South Asian (gnomAD v2.1.1 (Popmax MAF = 0.0004900 (0.049%), total alleles number = 15), gnomAD v4.0.0 (Popmax MAF = 0.0006492 (0.06492%), total alleles number = 56)). Variant is absent from other populations in gnomAD v2.1.1 and is found in only 1 case from Remaining population in gnomAD v4.0.0 (Popmax MAF = 0.00001656 ( 0.001656%)). We assume founder effect due to isolated occurrence in the South Asian population. For this reason, we excluded the SA population from PM2 assessment. PP3 - REVEL = 0.958. 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 3 index cases (1 case with DLCN criteria>=6 from Robarts Research Institute, Canada; 1 case with Simon-Broome criteria in PMID: 9259195 (Day et al., 1997), UK; 1 case with DLCN criteria>=6 in PMID: 11810272 (Fouchier et al., 2001), 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 = 0.958
PM2
Variant is found in South Asian (gnomAD v2.1.1 (Popmax MAF = 0.0004900 (0.049%), total alleles number = 15), gnomAD v4.0.0 (Popmax MAF = 0.0006492 (0.06492%), total alleles number = 56)). Variant is absent from other populations in gnomAD v2.1.1 and is found in only 1 case from Remaining population in gnomAD v4.0.0 (Popmax MAF = 0.00001656 ( 0.001656%)). We assume founder effect due to isolated occurrence in the South Asian population. For this reason, we excluded the SA population from PM2 assessment.
PS4_Supporting
Variant meets PM2 and is identified in 3 index cases (1 case with DLCN criteria>=6 from Robarts Research Institute, Canada; 1 case with Simon-Broome criteria in PMID: 9259195 (Day et al., 1997), UK; 1 case with DLCN criteria>=6 in PMID: 11810272 (Fouchier et al., 2001), 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
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
PVS1
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.980A>C (p.His327Pro) (ClinVar ID 918325) - Uncertain significance - insufficient evidence by these guidelines - NM_000527.5(LDLR):c.981C>A (p.His327Gln) (ClinVar ID 403665) - Uncertain significance - insufficient evidence 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
BS2
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
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
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
Curation History
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