7-107690200-G-C
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PM1PM2PM5PP3_StrongPP5_Very_Strong
The NM_000441.2(SLC26A4):c.1226G>C(p.Arg409Pro) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000248 in 1,611,862 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 12/21 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R409C) has been classified as Likely pathogenic.
Frequency
Consequence
NM_000441.2 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 18 ACMG points.
Transcripts
RefSeq
Ensembl
Frequencies
GnomAD3 genomes AF: 0.00000658 AC: 1AN: 151988Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.00000797 AC: 2AN: 250826Hom.: 0 AF XY: 0.0000148 AC XY: 2AN XY: 135534
GnomAD4 exome AF: 0.00000205 AC: 3AN: 1459874Hom.: 0 Cov.: 30 AF XY: 0.00000413 AC XY: 3AN XY: 726354
GnomAD4 genome AF: 0.00000658 AC: 1AN: 151988Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1AN XY: 74228
ClinVar
Submissions by phenotype
Autosomal recessive nonsyndromic hearing loss 4 Pathogenic:1
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not provided Pathogenic:1
This sequence change replaces arginine, which is basic and polar, with proline, which is neutral and non-polar, at codon 409 of the SLC26A4 protein (p.Arg409Pro). This variant is present in population databases (rs111033305, gnomAD 0.006%). This missense change has been observed in individual(s) with deafness (PMID: 12676893, 25266519). ClinVar contains an entry for this variant (Variation ID: 43497). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt SLC26A4 protein function with a positive predictive value of 95%. This variant disrupts the p.Arg409 amino acid residue in SLC26A4. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 11919333, 16053392, 19786220, 20597900, 24224479). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. -
Hearing loss, autosomal recessive Pathogenic:1
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Rare genetic deafness Pathogenic:1
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Pendred syndrome;C3538946:Autosomal recessive nonsyndromic hearing loss 4 Pathogenic:1
PP3, PM1, PM2, PM3, PM5 -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at