Submissions for variant NM_005982.4(SIX1):c.373G>A (p.Glu125Lys)

dbSNP: rs797044960

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV001852527	SCV002303355	likely pathogenic	Branchiootic syndrome 3; Autosomal dominant nonsyndromic hearing loss 23	2021-05-12	criteria provided, single submitter	clinical testing	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. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. This variant has been observed in individual(s) with SIX1-related conditions (PMID: 21700001). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 208361). This variant is not present in population databases (ExAC no frequency). This sequence change replaces glutamic acid with lysine at codon 125 of the SIX1 protein (p.Glu125Lys). The glutamic acid residue is highly conserved and there is a small physicochemical difference between glutamic acid and lysine.
3billion	RCV000190433	SCV002521893	likely pathogenic	Autosomal dominant nonsyndromic hearing loss 23	2022-05-22	criteria provided, single submitter	clinical testing	The variant is not observed in the gnomAD v2.1.1 dataset. Missense changes are a common disease-causing mechanism. In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.79; 3Cnet: 0.98). Same nucleotide change resulting in same amino acid change has been previously reported to be associated with SIX1 related disorder (ClinVar ID: VCV000208361 / PMID: 21700001).The variant has been reported to co-segregate with the disease in at least 5 similarly affected relatives/individuals in the same family or similarly affected unrelated families (PMID: 21700001). Therefore, this variant is classified as likely pathogenic according to the recommendation of ACMG/AMP guideline.
Laboratory of Otorhinolaryngology, Head and Neck Surgery, Seoul National University Hospital	RCV002478668	SCV003927056	likely pathogenic	Branchiootic syndrome 3	2023-05-05	criteria provided, single submitter	clinical testing
OMIM	RCV000190433	SCV000244273	pathogenic	Autosomal dominant nonsyndromic hearing loss 23	2011-09-01	no assertion criteria provided	literature only
GeneReviews	RCV002478668	SCV002775064	not provided	Branchiootic syndrome 3		no assertion provided	literature only