rs104894478
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PM1PM2PM5PP3_StrongPP5_Very_Strong
The NM_005982.4(SIX1):c.386A>G(p.Tyr129Cys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,461,880 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic 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. Y129S) has been classified as Likely pathogenic.
Frequency
Consequence
NM_005982.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 18 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
SIX1 | NM_005982.4 | c.386A>G | p.Tyr129Cys | missense_variant | 1/2 | ENST00000645694.3 | |
SIX1 | XM_017021602.3 | c.386A>G | p.Tyr129Cys | missense_variant | 1/2 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
SIX1 | ENST00000645694.3 | c.386A>G | p.Tyr129Cys | missense_variant | 1/2 | NM_005982.4 | P1 | ||
SIX1 | ENST00000554986.2 | c.42-2227A>G | intron_variant | 3 | |||||
SIX1 | ENST00000553535.2 | n.249-2227A>G | intron_variant, non_coding_transcript_variant | 3 | |||||
SIX1 | ENST00000555955.3 | n.1198-2227A>G | intron_variant, non_coding_transcript_variant | 2 |
Frequencies
GnomAD3 genomes ? Cov.: 32
GnomAD3 exomes AF: 0.00000398 AC: 1AN: 251416Hom.: 0 AF XY: 0.00 AC XY: 0AN XY: 135904
GnomAD4 exome AF: 0.00000137 AC: 2AN: 1461880Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0AN XY: 727242
GnomAD4 genome ? Cov.: 32
ClinVar
Submissions by phenotype
not provided Pathogenic:3
Pathogenic, no assertion criteria provided | clinical testing | Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center | - | - - |
Pathogenic, no assertion criteria provided | clinical testing | Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+ | - | - - |
Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Jun 29, 2023 | Observed in multiple unrelated patients from different ethnic backgrounds with clinical features of branchiootorenal spectrum disorder (Ruf et al., 2004; Ito et al., 2006; Krug et al., 2011; Noguchi et al., 2011); Published functional studies demonstrate a damaging effect with deficient DNA binding (Ruf et al., 2004; Patrick et al., 2009); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 15141091, 19497856, 34208995, 31980437, 31595699, 16652090, 21280147, 21254961, 25326635) - |
Branchiootic syndrome 3 Pathogenic:2Other:1
Pathogenic, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Jul 15, 2022 | Variant summary: SIX1 c.386A>G (p.Tyr129Cys) results in a non-conservative amino acid change located in the Homeobox domain (IPR001356) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 4e-06 in 251416 control chromosomes (gnomAD). c.386A>G has been reported in the literature in multiple individuals affected with Branchiootic Syndrome 3 and fully co-segregated with disease in a large kindred (Ruf_2004, Ito_2006, Noguchi_2011, Nishio_2015). These data indicate that the variant is very likely to be associated with disease. Experimental evidence evaluating an impact on protein function demonstrated the variant significantly reduced the binding activity of Six1 to DNA, and inhibited the ability of the SIX1-EYA complex to activate transcription (Ruf_2004, Patrick_2009). Three ClinVar submitters (evaluation after 2014) cite the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. - |
Pathogenic, no assertion criteria provided | literature only | OMIM | May 25, 2004 | - - |
not provided, no classification provided | literature only | GeneReviews | - | - - |
Branchiootic syndrome 3;C1854594:Autosomal dominant nonsyndromic hearing loss 23;C4551702:Branchiootorenal syndrome 1 Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Oct 31, 2018 | - - |
Branchiootic syndrome 3;C1854594:Autosomal dominant nonsyndromic hearing loss 23 Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Dec 23, 2023 | This sequence change replaces tyrosine, which is neutral and polar, with cysteine, which is neutral and slightly polar, at codon 129 of the SIX1 protein (p.Tyr129Cys). This variant is present in population databases (rs104894478, gnomAD 0.007%). This missense change has been observed in individuals with branchiootorenal spectrum disorders (PMID: 12843324, 15141091, 16652090, 21254961, 21280147). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 8308). 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 SIX1 protein function with a positive predictive value of 80%. Experimental studies have shown that this missense change affects SIX1 function (PMID: 15141091, 19497856). For these reasons, this variant has been classified as Pathogenic. - |
Autosomal dominant nonsyndromic hearing loss 23 Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Sep 01, 2017 | This variant has been previously reported as disease-causing and was found once in our laboratory de novo in a 5-year-old female with bilateral mild-to-moderate sensorineural hearing loss & preauricular pits; father & paternal grandfather had adult-onset conductive hearing loss; mother had preauricular pit - |
SIX1-related disorder Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | PreventionGenetics, part of Exact Sciences | Nov 15, 2023 | The SIX1 c.386A>G variant is predicted to result in the amino acid substitution p.Tyr129Cys. This variant has been reported to segregate with branchiootic syndrome (BOS) in one large family with 18 affected individuals and was also found in two additional individuals with BOS from two unrelated families (Ruf et al. 2004. PubMed ID: 15141091; Ito et al. 2006. PubMed ID: 16652090; Noguchi et al. 2011. PubMed ID: 21254961). Functional experiments found this variant reduced DNA binding activity (Ruf et al. 2004. PubMed ID: 15141091; Patrick et al. 2009. PubMed ID: 19497856). This variant is reported in 0.0062% of alleles in individuals of African descent in gnomAD (http://gnomad.broadinstitute.org/variant/14-61115522-T-C). This variant is interpreted as likely pathogenic. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at