Evidence Repository - Clinical Genome Resources

The ClinGen Evidence Repository is an FDA-recognized human genetic variant database containing expert-curated assertions regarding variants' pathogenicity and supporting evidence summaries. [Disclaimer]

Variant: NM_000527.5(LDLR):c.1916T>G (p.Val639Gly)

Curation Version - 1.0
Curation History
JSON LD for Version 1.0

CA10585680

252112 (ClinVar)

Gene: LDLR

Condition: hypercholesterolemia, familial

Inheritance Mode: Semidominant inheritance

Link to MONDO

UUID: 7eb59b6b-800b-402f-860c-ac967bfe5cfb

Approved on: 2025-01-31

Published on: 2025-03-09

HGVS expressions

NM_000527.5:c.1916T>G

NM_000527.5(LDLR):c.1916T>G (p.Val639Gly)

NC_000019.10:g.11120162T>G

CM000681.2:g.11120162T>G

NC_000019.9:g.11230838T>G

CM000681.1:g.11230838T>G

NC_000019.8:g.11091838T>G

NG_009060.1:g.35782T>G

ENST00000252444.10:c.2174T>G

ENST00000559340.2:c.1776T>G

ENST00000560467.2:c.1796T>G

ENST00000558518.6:c.1916T>G

ENST00000252444.9:c.2170T>G

ENST00000455727.6:c.1412T>G

ENST00000535915.5:c.1793T>G

ENST00000545707.5:c.1535T>G

ENST00000557933.5:c.1916T>G

ENST00000558013.5:c.1916T>G

ENST00000558518.5:c.1916T>G

ENST00000559340.1:c.497T>G

NM_000527.4:c.1916T>G

NM_001195798.1:c.1916T>G

NM_001195799.1:c.1793T>G

NM_001195800.1:c.1412T>G

NM_001195803.1:c.1535T>G

NM_001195798.2:c.1916T>G

NM_001195799.2:c.1793T>G

NM_001195800.2:c.1412T>G

NM_001195803.2:c.1535T>G

Likely Pathogenic

PP4 PP1_Strong PM2 PM5

BP7 BP2 BP4 PS4 PS1 PS2 PS3 PP3 PVS1 PM6 PM3 PM4 PM1 BA1 BS2 BS4 BS3 BS1

Evidence Links 0

Expert Panel

Familial Hypercholesterolemia VCEP

Criteria Specification Information

Criteria Specification: ClinGen Familial Hypercholesterolemia Expert Panel Specifications to the ACMG/AMP Variant Classification Guidelines Version 1.2

PDF

Criteria Specification Approval History

Criteria Specifications for this VCEP

Evidence submitted by expert panel

Familial Hypercholesterolemia VCEP

The NM_000527.5(LDLR):c.1916T>G (p.Val639Gly) variant is classified as Likely Pathogenic for Familial Hypercholesterolemia by applying ACMG/AMP evidence codes PP1_Strong, PM2, PM5 and PP4 as defined by the ClinGen Familial Hypercholesterolemia Expert Panel LDLR-specific variant curation guidelines (specification version 1.2) on January 31, 2025. The supporting evidence is as follows: PM2: PopMax MAF = 0.00002196 (0.002196%) in South Asian exomes+genomes (gnomAD v4.1.0). PM5: 1 other missense variant in the same codon is classified as Pathogenic by these guidelines: - NM_000527.5(LDLR):c.1916T>A (p.Val639Asp) (ClinVar ID 200922). PP4: Variant meets PM2 and is identified in only 1 proband with MEDPED criteria for FH from Pakistan (PMID 22311046 – Ahmed et al., 2012), after alternative causes of high cholesterol were excluded. PP1_Strong: Variant segregates with FH phenotype in 9 informative meiosis from 1 family from Pakistan (PMID 22311046 – Ahmed et al., 2012): 6 affected family members have the variant and 3 unaffected family members do not have the variant.

PP4

Variant meets PM2 and is identified in only 1 proband with MEDPED criteria for FH from Pakistan (PMID: 22311046), so PP4 is met.

PP1_Strong

Variant segregates with FH phenotype in 9 informative meiosis from 1 family from Pakistan ( PMID: 22311046): 6 affected family members have the variant and 3 non-affected family members do not have the variant, so PP1_Strong is met.

PM2

PopMax MAF = 0.00002196 (0.002196%) in South Asian exomes+genomes (gnomAD v4.1.0), so PM2 is met.

PM5

1 other missense variant in the same codon: - NM_000527.5(LDLR):c.1916T>A (p.Val639Asp) (ClinVar ID 200922) - Pathogenic by these guidelines There is 1 variant in the same codon classified as Pathogenic by these guidelines.

BP7

Variant is not synonymous, so BP7 is Not Met.

BP2

Cannot determine if the proband LDL-C=230 mg/dL is untreated.

BP4

REVEL = 0.681, it is not below 0.50, so BP4 is not met.

PS4

Variant meets PM2 and is identified in only 1 proband with MEDPED criteria for FH from Pakistan (PMID: 22311046), so PS4 is not met.

PS1

No more missense variants that lead to the same amino acid change, so PS1 is Not Met.

PS2

de novo occurrence data not reported, so PS2 is Not Met.

PS3

There are no functional studies reported for this variant, so PS3 is not met.

PP3

REVEL = 0.681, it is not above 0.75, splicing evaluation required. Functional data on splicing not available. A) variant not on limits B) does not create AG or GT C) no AG/GT nearby Variant is not predicted to alter splicing, so PP3 is Not Met.

PVS1

Variant is missense, so PVS1 is Not Met.

PM6

de novo occurrence data not reported, so PM6 is Not Met.

PM3

Variant meets PM2 and is identified in a proband homozygous for c.1916T>G/p.(Val639Gly), however, patient's LDL-C is 230 mg/dL and there is no indication of lipid-lowering medication, so PM3 not met.

PM4

Variant meets PM2 and is missense, so PM4 is Not Met.

PM1

Variant meets PM2 but is not located in exon 4 or alters a cysteine residue, so PM1 is Not Met.

BA1

FAF = 0.000003850 (0.0003850%) in South Asian exomes+genomes (gnomAD v4.1.0), so BA1 is Not Met.

BS2

Not detected in 100 healthy control individuals, so BS2 is not met.

BS4

Lack of segregation data not reported, so BS4 is Not Met.

BS3

There are no functional studies reported for this variant, so BS3 is not met.

BS1

FAF = 0.000003850 (0.0003850%) in South Asian exomes+genomes (gnomAD v4.1.0), so BS1 is Not Met.

Curation History

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