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_000551.4(VHL):c.376G>A (p.Asp126Asn)

CA020313

141044 (ClinVar)

Gene: VHL
Condition: von Hippel-Lindau disease
Inheritance Mode: Autosomal dominant inheritance
Link to MONDO
UUID: 4bbaddce-62df-48bb-887c-dfc95d16ce87
Approved on: 2024-06-25
Published on: 2024-06-25

HGVS expressions

NM_000551.4:c.376G>A
NM_000551.4(VHL):c.376G>A (p.Asp126Asn)
NC_000003.12:g.10146549G>A
CM000665.2:g.10146549G>A
NC_000003.11:g.10188233G>A
CM000665.1:g.10188233G>A
NC_000003.10:g.10163233G>A
NG_008212.3:g.9915G>A
ENST00000696142.1:c.*53G>A
ENST00000696143.1:c.600-3238G>A
ENST00000696153.1:c.376G>A
ENST00000256474.3:c.376G>A
ENST00000256474.2:c.376G>A
ENST00000345392.2:c.341-3238G>A
ENST00000477538.1:n.512G>A
NM_000551.3:c.376G>A
NM_198156.2:c.341-3238G>A
NM_001354723.1:c.*18-3238G>A
NM_001354723.2:c.*18-3238G>A
NM_198156.3:c.341-3238G>A

Uncertain Significance

Met criteria codes 4
PS4_Moderate BS1 PP3 PM1
Not Met criteria codes 2
BP4 PS3

Evidence Links 0

Expert Panel

Criteria Specification Information

Criteria Specification: ClinGen VHL Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for VHL Version 1.0.0

Criteria Specification Approval History
Criteria Specifications for this VCEP
Evidence submitted by expert panel
VHL VCEP
The variant NM_000551.4(VHL):c.376G>A (p.Asp126Asn) is a missense variant predicted to cause substitution of Aspartic acid by Asparagine at position 126. The GroupMax Filtering Allele Frequency (95% CI) in gnomAD v4.1.0 is 0.00003260 (50/1111878 from European, Non-Finnish Population). This is higher than the ClinGen VHL VCEP threshold of >=0.0000156 (0.00156%) threshold expected for VHL disease (BS1). However, this variant fulfills several pathogenic evidence codes as follows. This variant has been reported in 1 proband in literature, a 53yo male with right jugulotympanic paraganglioma (nonspecific = 0.25 points) (PMID: 22566194). This variant has been seen 12 times in testing at Invitae with 3 cases bearing VHL tumors, 3 times at GeneDX with no cases presenting VHL tumors, and 19 times at Ambry with 2 cases including VHL tumors. For the observed cases without VHL spectrum tumors, they either had no personal history of cancer or non-VHL cancers. None were >65yo and lacked VHL-spectrum tumors. In total, the case points calculated are 2.5 points which sums to PS4_Moderate. One HIF-a degradation assay using this variant showed modest / intermediate inability to degrade HIF-a (PMIDs:21454469), but does not meet the criteria for PS3_Supporting. This variant resides within a region of VHL that is defined as a critical functional domain (the Beta Domain) (PM1). The computational predictor REVEL gives a score of 0.716, which is above the threshold of >0.664, evidence that correlates with impact to VHL function (PP3). In summary, due to the prevalence of this variant in the gnomAD and numerous cases lacking VHL tumors (though not above the threshold of 65yrs to fulfill the benign criteria) as well as weak/intermediate functional evidence, this variant meets the criteria to be classified as Uncertain for autosomal-dominant von Hippel Lindau syndrome (VHL syndrome) based on the ACMG/AMP criteria applied, as specified by the ClinGen VHL VCEP Version 1.0 (Specifications approval date: 02/26/2024. Variant Approval Date 06/25/2024).
Met criteria codes
PS4_Moderate
This variant has been reported in 1 proband in literature (a 53yo male with right jugulotympanic paraganglioma (nonspecific = 0.25 points) (PMID: 22566194). This variant has been seen 12 times in testing at Invitae with 3 cases bearing VHL tumors, 3 times at GeneDX with no cases presenting VHL tumors, and 19 times at Ambry with 2 cases including VHL tumors. For the observed cases without VHL spectrum tumors, they either had no personal history of cancer or non-VHL cancers. None were >65yo and lacked VHL-spectrum tumors. In total, the case points calculated are 2.5 points which sums to PS4_Moderate.
BS1
The GroupMax Filtering Allele Frequency (95% CI) in gnomAD v4.1.0 is 0.00003260 (50/1111878 from European, Non-Finnish Population). This is higher than the ClinGen VHL VCEP threshold of >=0.0000156 (0.00156%) threshold expected for VHL disease (BS1).
PP3
The computational predictor REVEL gives a score of 0.716, which is above the threshold of >0.664, evidence that correlates with impact to VHL function (PP3).
PM1
This variant resides within a region of VHL that is defined as a critical functional domain (the Beta Domain) (PM1).
Not Met criteria codes
BP4
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
PS3
While Bond J et al. shows that D126N has a modest effect leading to loss of HIF1a degradation, this was seen in a pediatric case with severe erythropoietic dysregulation and PAH who is a compound heterozygote for novel VHL mutations -- and did not have noted VHL phenotype or cancers or a history of inherited VHL. A second source (PMID: 30338240) cites the work of Bond et al for the HIF1a degradation assay and does not replicate the work. Thus this does not meet the criteria of showing complete loss of HIF1a degradation and does not meet PS3_Supporting.
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