rs80356460
Variant summary
Our verdict is Pathogenic. Variant got 13 ACMG points: 13P and 0B. PM1PM2PM4_SupportingPP5_Very_Strong
The NM_005982.4(SIX1):c.397_399delGAG(p.Glu133del) variant causes a conservative inframe deletion change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,461,870 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely pathogenic (★★).
Frequency
Consequence
NM_005982.4 conservative_inframe_deletion
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 13 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
SIX1 | NM_005982.4 | c.397_399delGAG | p.Glu133del | conservative_inframe_deletion | Exon 1 of 2 | ENST00000645694.3 | NP_005973.1 | |
SIX1 | NM_001425142.1 | c.397_399delGAG | p.Glu133del | conservative_inframe_deletion | Exon 1 of 2 | NP_001412071.1 | ||
MIR9718 | NR_162089.1 | n.*80_*82delCTC | downstream_gene_variant | |||||
MIR9718 | unassigned_transcript_2330 | n.*91_*93delCTC | downstream_gene_variant |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
SIX1 | ENST00000645694.3 | c.397_399delGAG | p.Glu133del | conservative_inframe_deletion | Exon 1 of 2 | NM_005982.4 | ENSP00000494686.1 | |||
SIX1 | ENST00000554986.2 | c.42-2216_42-2214delGAG | intron_variant | Intron 1 of 1 | 3 | ENSP00000452700.2 | ||||
SIX1 | ENST00000553535.2 | n.249-2216_249-2214delGAG | intron_variant | Intron 2 of 2 | 3 | |||||
SIX1 | ENST00000555955.3 | n.1198-2216_1198-2214delGAG | intron_variant | Intron 1 of 1 | 2 |
Frequencies
GnomAD3 genomes Cov.: 32
GnomAD4 exome AF: 0.00000137 AC: 2AN: 1461870Hom.: 0 AF XY: 0.00000138 AC XY: 1AN XY: 727236
GnomAD4 genome Cov.: 32
ClinVar
Submissions by phenotype
Branchiootic syndrome 3 Pathogenic:4Other:1
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The variant is not observed in the gnomAD v2.1.1 dataset. Inframe deletion located in a nonrepeat region is predicted to change the length of the protein and disrupt normal protein function. Functional studies provide moderate evidence of the variant having a damaging effect on the gene or gene product (PMID: 19497856). The variant has been reported to be associated with SIX1-related disorder (ClinVar ID: VCV000008310 / PMID: 15141091). Therefore, this variant is classified as Likely pathogenic according to the recommendation of ACMG/AMP guideline. -
This variant was found in heterozygosity in a patient and their mother, both with bilateral sensorineural hearing loss of onset <18 years, in a study of pediatric hearing loss conducted by the King Laboratory (Carlson RJ et al. JAMA-OtoHNS 2023). At the time of recruitment, both patients had preauricular ear pits, but had no other signs associated with branchio-oto-renal syndrome. This family has no other history of hearing loss outside of the proband and their mother. This variant is a three base pair deletion that results in the deletion of the glutamine residue at position 133 of the SIX1 protein. As of January 2023, this variant has been reported to ClinVar as pathogenic/likely pathogenic and is not found on gnomAD. Based on co-segregation with the phenotype in the family and goodness of fit of genotype to phenotype, we conclude that this variant is likely pathogenic. -
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Branchiootic syndrome 3;C1854594:Autosomal dominant nonsyndromic hearing loss 23 Pathogenic:1
This variant has been observed in individuals with branchiootorenal spectrum conditions and/or early onset deafness (PMID: 15141091, 36633841; Invitae). It has also been observed to segregate with disease in related individuals. This variant is not present in population databases (gnomAD no frequency). This variant, c.397_399del, results in the deletion of 1 amino acid(s) of the SIX1 protein (p.Glu133del), but otherwise preserves the integrity of the reading frame. This variant is also known as delE133. 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. Experimental studies have shown that this variant affects SIX1 function (PMID: 15141091, 19497856, 23435380). Algorithms developed to predict the effect of variants on protein structure and function are not available or were not evaluated for this variant. ClinVar contains an entry for this variant (Variation ID: 8310). -
not provided Pathogenic:1
Functional studies demonstrate a damaging effect; variant results in diminished DNA binding and decreased lacZ activity (Ruf RG et al., 2004; Patrick AN et al., 2009); In-frame deletion of 1 amino acid in a non-repeat region; Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 15141091, 19497856, 33105617, 31595699) -
Autosomal dominant nonsyndromic hearing loss 23 Pathogenic:1
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Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at