Submissions for variant NM_000441.2(SLC26A4):c.1262A>G (p.Gln421Arg) (rs201660407)

Total submissions: 2

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000494508	SCV000582987	likely pathogenic	not provided	2018-12-11	criteria provided, single submitter	clinical testing	The Q421R variant in the SLC26A4 gene has been reported as a single heterozygous variant in an individual with hearing loss (Landa et al., 2013). It was also identified in another individual with a reported clinical diagnosis of Pendred syndrome; it was not specified whether this individual harbored a second SLC26A4 variant (Prasad et al., 2004). The Q421R variant was not observed at a significant frequency in large population cohorts (Lek et al., 2016). The Q421R variant is a semi-conservative amino acid substitution, which may impact secondary protein structure as these residues differ in some properties. In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect. Other missense variants at the same residue (Q421K, Q421P, Q421L) and missense variants nearby residues (T420I, V422I, V422D, G424D, I426N ) have been reported in the Human Gene Mutation Database in association with SLC26A4-related disorders (Stenson et al., 2014), supporting the functional importance of this residue and this region of the protein. Therefore, we classify this variant as likely pathogenic.
Counsyl	RCV000673206	SCV000798383	uncertain significance	Pendred syndrome	2018-03-07	criteria provided, single submitter	clinical testing