Variant: NM_000551.4(VHL):c.341-25_370dup

CA040509

411994 (ClinVar)

Gene: VHL

Condition: von Hippel-Lindau disease

Inheritance Mode: Autosomal dominant inheritance

UUID: 6040a579-be71-4c55-b0d9-820bc8ccb0f9

Approved on: 2024-06-25

Published on: 2024-06-25

HGVS expressions

NM_000551.4:c.341-25_370dup
NM_000551.4(VHL):c.341-25_370dup
NC_000003.12:g.10146489_10146543dup
CM000665.2:g.10146489_10146543dup
NC_000003.11:g.10188173_10188227dup
CM000665.1:g.10188173_10188227dup
NC_000003.10:g.10163173_10163227dup
NG_008212.3:g.9855_9909dup
ENST00000696142.1:c.*18-25_*47dup
ENST00000696143.1:c.600-3298_600-3244dup
ENST00000696153.1:c.341-25_370dup
ENST00000256474.3:c.341-25_370dup
ENST00000256474.2:c.341-25_370dup
ENST00000345392.2:c.341-3298_341-3244dup
ENST00000477538.1:n.477-25_506dup
NM_000551.3:c.341-25_370dup
NM_198156.2:c.341-3298_341-3244dup
NM_001354723.1:c.*18-3298_*18-3244dup
NM_001354723.2:c.*18-3298_*18-3244dup
NM_198156.3:c.341-3298_341-3244dup

Uncertain Significance

• Met criteria codes: PVS1_Strong

• Not Met criteria codes: BS1 PS4

Expert Panel

VHL VCEP

Criteria Specification Information

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

Evidence submitted by expert panel

VHL VCEP

NM_000551.4(VHL):c.341-25_370dup is a 55bp tandem duplication that contains part of the intron between Exon 1 and contains AA115-124 of Exon 2 (chr3:10,146,489-10,146,543, hg38). This is is presumed to disrupt the reading frame as well as add intronic sequence to the coding region, and results in an early truncation 26 amino acids downstream. This region is predicted to undergo Nonsense Mediated Decay. (PVS1_Strong). One of three commercial laboratories reports 1 case with this variant, and the case does not harbor VHL spectrum tumors. One academic laboratory reports 1 case with this variant. Case 1 (0.5 points) : a proband with pheochromocytoma, father and sibling both had RCC (but their VHL variant status is not confirmed). (PS4_NotMet). The GroupMax Filtering Allele Frequency (95% CI) in gnomAD v4.1.0 is 0.000001830 (6/1179074 from European, Non-Finnish Population). This is lower than the ClinGen VHL VCEP threshold expected for VHL disease, of <=0.0000156 (0.00156%) for BS1, and therefore does not meet any population criterion (BS1, BA1, PM2_Supporting are not met). In summary, 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

• PVS1_Strong: This 55bp tandem duplication contains part of the intron between Exon 1 and contains AA115-124 of Exon 2 (chr3:10,146,489-10,146,543, hg38). This is is presumed to disrupt the reading frame as well as add intronic sequence to the coding region, and results in an early truncation 26 amino acids downstream. This region is predicted to undergo Nonsense Mediated Decay. (PVS1_Strong).

Not Met criteria codes

• BS1: The GroupMax Filtering Allele Frequency (95% CI) in gnomAD v4.1.0 is 0.000001830 (6/1179074 from European, Non-Finnish Population). This is lower than the ClinGen VHL VCEP threshold expected for VHL disease, of <=0.0000156 (0.00156%) for BS1, and therefore does not meet any criterion (BS1, BA1, PM2_Supporting are not met).
• PS4: One of three commercial laboratories reports 1 case with this variant, and the case does not harbor VHL spectrum tumors. One academic laboratory reports 1 case with this variant. Case 1 (0.5 points) : a proband with pheochromocytoma, father and sibling both had RCC (but their VHL variant status is not confirmed).