Submissions for variant NM_000238.4(KCNH2):c.3007G>A (p.Asp1003Asn)

gnomAD frequency: 0.00002  dbSNP: rs794728402

Total submissions: 3

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000413178	SCV000492233	uncertain significance	not specified	2016-11-29	criteria provided, single submitter	clinical testing	A variant of uncertain significance has been identified in the KCNH2 gene. The D1003N variant has been previously reported in one Japanese individual from a cohort of individuals with acquired LQTS, who were found to have a prolonged QT interval and Torsades de Pointes ventricular tachycardia triggered by drugs, hypokalemia or bradycardia (Itoh et al., 2016). However, this individual harbored an additional cardiogenetic variant, and further clinical details and segregation studies were not described. The D1003N variant was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project (average read depth 7X). Furthermore, this substitution occurs at a position where amino acids with similar properties to Aspartic acid are tolerated across species, and D1003N is a semi-conservative amino acid substitution, which may impact secondary protein structure as these residues differ in some properties. Nevertheless, in silico analysis is inconsistent in its predictions as to whether or not the variant is damaging to the protein structure/function.Therefore, based on the currently available information, it is unclear whether this variant is pathogenic or rare benign.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000631725	SCV000752813	uncertain significance	Long QT syndrome	2022-10-17	criteria provided, single submitter	clinical testing	In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C0"). ClinVar contains an entry for this variant (Variation ID: 373622). This missense change has been observed in individual(s) with acquired long QT syndrome (LQTS) (PMID: 26715165). This variant is present in population databases (no rsID available, gnomAD 0.01%). This sequence change replaces aspartic acid, which is acidic and polar, with asparagine, which is neutral and polar, at codon 1003 of the KCNH2 protein (p.Asp1003Asn).
Ambry Genetics	RCV002436239	SCV002748867	uncertain significance	Cardiovascular phenotype	2022-06-22	criteria provided, single submitter	clinical testing	The p.D1003N variant (also known as c.3007G>A), located in coding exon 13 of the KCNH2 gene, results from a G to A substitution at nucleotide position 3007. The aspartic acid at codon 1003 is replaced by asparagine, an amino acid with highly similar properties. This alteration has been reported in a long QT syndrome cohort; however, clinical details were limited and an additional alteration in an associated gene was also identified (Itoh H et al. Eur Heart J, 2016 May;37:1456-64). This amino acid position is not well conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.