Submissions for variant NM_005982.4(SIX1):c.386A>G (p.Tyr129Cys)

dbSNP: rs104894478

Total submissions: 10

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000413341	SCV000490796	pathogenic	not provided	2023-06-29	criteria provided, single submitter	clinical testing	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)
Baylor Genetics	RCV000679883	SCV000807279	pathogenic	Autosomal dominant nonsyndromic hearing loss 23	2017-09-01	criteria provided, single submitter	clinical testing	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
Fulgent Genetics, Fulgent Genetics	RCV000763344	SCV000894029	pathogenic	Branchiootic syndrome 3; Autosomal dominant nonsyndromic hearing loss 23; Branchiootorenal syndrome 1	2018-10-31	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000008806	SCV002570804	pathogenic	Branchiootic syndrome 3	2022-07-15	criteria provided, single submitter	clinical testing	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.
Invitae	RCV002512918	SCV003442337	pathogenic	Branchiootic syndrome 3; Autosomal dominant nonsyndromic hearing loss 23	2023-12-23	criteria provided, single submitter	clinical testing	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.
PreventionGenetics, part of Exact Sciences	RCV003390661	SCV004112716	likely pathogenic	SIX1-related condition	2023-11-15	criteria provided, single submitter	clinical testing	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.
OMIM	RCV000008806	SCV000029016	pathogenic	Branchiootic syndrome 3	2004-05-25	no assertion criteria provided	literature only
GeneReviews	RCV000008806	SCV000086936	not provided	Branchiootic syndrome 3		no assertion provided	literature only
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV000413341	SCV001952829	pathogenic	not provided		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV000413341	SCV001973075	pathogenic	not provided		no assertion criteria provided	clinical testing