HGVS description for intragenic TECRL exons 5–7 tandem duplication (CNV, GRCh37)

[Alvaro Reyes]

Dear HGVS nomenclature team,

I would appreciate your advice on the correct HGVS description for an intragenic tandem duplication in TECRL reported in a recent paper.

The variant is from:

Jones D et al. “Novel variants in TECRL leading to catecholaminergic polymorphic ventricular tachycardia.” Life Science Alliance 2024; DOI: 10.26508/lsa.202402572.

Context from the paper

• Sequencing: rapid whole-genome sequencing (rWGS) performed as a clinical test (Illumina PCR-free libraries, NovaSeq 6000, paired-end).

• Reference: GRCh37.

• Alignment/variant calling: DRAGEN Bio-IT; analysis with Fabric Enterprise.

• Both SNVs/indels and CNVs were called; CNVs were filtered to retain events overlapping or with a boundary within 1 kb of an exon and were classified with ACMG CNV guidelines.

• The patient had:

  1. A maternally inherited nonsense variant in TECRL, reported as c.915T>G (p.Tyr305Ter).

  2. An additional intragenic duplication in TECRL, identified by the CNV pipeline and described as:

     • chr4:65165944–65185287, dup [4q13.1], size ~19 kb, heterozygous, copy number “x3” in their Table 2.

• The authors state that this duplication “encompasses exons 5–7 of the TECRL gene” and that manual inspection of reads supports a tandem duplication.

• They interpret it as loss-of-function (truncation or NMD).

• Orthogonal confirmation: the structural variant (this duplication) was confirmed by MLPA in the proband and was not present in the mother; the father was unavailable.

Gene / transcript

• Gene: TECRL (4q13.1, reverse strand).

• For the nonsense variant I am using MANE Select NM_001010874.5(TECRL):c.915T>G.

My questions concern the best way to represent this exons 5–7 tandem duplication in HGVS.

For this TECRL duplication, would you recommend something like:

• NC_000004.11:g.(65165944_65185287)dup

to indicate a tandem duplication with imprecise breakpoints?

I also need to represent the same variant on GRCh38. Using standard coordinate conversion for the TECRL locus, the interval maps approximately to:

• chr4:64,300,226–64,319,569 on GRCh38 (NC_000004.12).

Would the analogous HGVS description for GRCh38 be something like:

• NC_000004.12:g.(64300226_64319569)dup

Thanks for your help and best regards, 

Álvaro E. Reyes Quintero, MD

Universidad de Guadalajara 

Doctorado en Genética Humana  

[Johan den Dunnen]

Dear Alvaro,

HGVS nomenclature uses a 4-position format to describe duplications where the breakpoint has not been sequenced. The description defines the minimal and maximal extent of the variant. When the paper describes the variant as chr4:65165944–65185287x3 it seems best to assume the positions given define the minimal extent of the duplication. The variant should then be described as NC_000004.11:g.(?_65165944)_(65185287_?)dup (linking to NC_000004.12:g.(?_64300226)_(64319569_?)dup). I noticed the case is reported in the TECRL gene variant LOVD database (see https://databases.lovd.nl/shared/variants/0001059547). Checking gene variant databases sometimes helps to see how variants are reported using different formats.

Best regards,

Johan den Dunnen
HUGO HGVS Variant Nomenclature Committee (HVNC)

Op dinsdag 18 november 2025 om 06:32:52 UTC+1 schreef alvaroe...@gmail.com: