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
Labcorp Genetics (formerly Invitae), Labcorp	RCV001852527	SCV002303355	pathogenic	Branchiootic syndrome 3; Autosomal dominant nonsyndromic hearing loss 23	2024-05-20	criteria provided, single submitter	clinical testing	This sequence change replaces glutamic acid, which is acidic and polar, with lysine, which is basic and polar, at codon 125 of the SIX1 protein (p.Glu125Lys). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with clinical features of SIX1-related conditions (PMID: 21700001, 37479820). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 208361). 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: 37479820). For these reasons, this variant has been classified as Pathogenic.
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