21-34449498-T-C
Variant summary
Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PM1PP3_ModeratePP5
The NM_000219.6(KCNE1):āc.137A>Gā(p.Tyr46Cys) variant causes a missense change. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).
Frequency
Consequence
NM_000219.6 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Uncertain_significance. Variant got 5 ACMG points.
Transcripts
RefSeq
Ensembl
Frequencies
GnomAD3 genomes Cov.: 14
GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.00000101 AC: 1AN: 988036Hom.: 0 Cov.: 21 AF XY: 0.00 AC XY: 0AN XY: 498238
GnomAD4 genome Cov.: 14
ClinVar
Submissions by phenotype
not provided Pathogenic:1
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Rare genetic deafness Pathogenic:1
The p.Tyr46Cys variant in KCNE1 has been identified by our laboratory in the hom ozygous state in 1 individual with clinical features of Jervell and Lange-Nielse n syndrome (JLNS) and segregated in an affected sibling. This variant has been identified in 1/3494 Finnish chromosomes by the Genome Aggregation Database (gno mAD, http://gnomad.broadinstitute.org). Computational prediction tools and conse rvation analyses suggest that this variant may impact the protein, though this i nformation is not predictive enough to determine pathogenicity. In summary, alth ough additional studies are required to fully establish its clinical significanc e, this variant is likely pathogenic for autosomal recessive JLNS. -
Cardiovascular phenotype Uncertain:1
The p.Y46C variant (also known as c.137A>G), located in coding exon 1 of the KCNE1 gene, results from an A to G substitution at nucleotide position 137. The tyrosine at codon 46 is replaced by cysteine, an amino acid with highly dissimilar properties. This alteration has been reported in a long QT syndrome cohort; however, clinical details were limited (Roberts JD et al. Circulation, 2020 Feb;141:429-439). Limited functional studies have suggested this alteration may impact current amplitudes and pore conductance (Wang Y et al. J. Gen. Physiol., 2012 Dec;140:653-69). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -
Long QT syndrome 5 Other:1
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Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at