Short QT syndrome

Gene: SLC4A3

Green List (high evidence)

PMID: 36806574
- Cohort of patients with suspected SQTS, all index patients fulfilling a clinical diagnosis of SQTS according to the European Society of Cardiology 2015 guideline criteria.
- Missense R370H (same variant in PMID: 29167417) in one German family, and four other missense variants (p.Arg600Cys, p.Arg621Trp, p.Glu852Asp, and p.Arg952His) in three German families and one Danish family. (Variants were annotated in NM_201574.2)
- The Arg952His also segregated in proband’s brother with QTc interval of 320ms.
- Knockdown of slc4a3 in zebrafish resulted in shortened heart rate-corrected QT intervals that could be rescued by overexpression of the native human SLC4A3-encoded protein (AE3), but neither by the mutated AE3 variants p.Arg600Cys, p.Arg621Trp, p.Glu852Asp nor by p.Arg952His, suggesting pathogenicity of these variants.
- Three of these missense are absent in gnomAD (v2, v3), one has only 1 het in gnomAD (v2).

Created: 20 Jul 2023, 7:41 a.m. | Last Modified: 20 Jul 2023, 7:41 a.m.

Panel Version: 1.5

Mode of inheritance
MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted

Phenotypes
Short QT syndrome 7, MIM#620231

Publications

• 36806574

Variants in this GENE are reported as part of current diagnostic practice

I don't know

Note same variant identified in both families ?founder. Amber rating for now.

Created: 11 Oct 2021, 5:51 a.m. | Last Modified: 11 Oct 2021, 5:51 a.m.

Panel Version: 0.6

Mode of inheritance
MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted

Phenotypes
Short QT syndrome 7, MIM#620231

Green List (high evidence)

Moderate evidence for autosomal dominant short QT syndrome 1 by ClinGen /gene curation expert panel (PMID: 34557911). A single missense variant (absent gnomAD) identified in two SQTS families. In family 1, it segregated with SQTS (QTc<370ms) in 23 carriers, and 19 non-carriers had a QTc>370ms. In family 2, it segregated in 4 individuals. Experimental evidence from in vitro and zebrafish models suggests reduced membrane localization of the mutated protein leads to intracellular alkalinization and shortening of the cardiomyocyte action potential duration.
ClinGen expert panel was divided between strong (4 votes) and moderate (5 votes).
Sources: Expert Review

Created: 11 Oct 2021, 3:52 a.m.

Mode of inheritance
MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted

Phenotypes
Short QT syndrome

Publications

• PMID: 29167417
• 34557911