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

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen Hearing Loss Variant Curation Expert Panel	RCV000673206	SCV001164273	likely pathogenic	Pendred syndrome	2019-10-22	reviewed by expert panel	curation	The c.1262A>G (p.Gln421Arg) variant in SLC26A4 is present in 0.002653% of non-Finnish European alleles in gnomAD (PM2; https://gnomad.broadinstitute.org). This variant was observed in 1 individual with hearing loss and either dilated vestibular aqueduct or Mondini dysplasia, which are consistent for Pendred syndrome, a condition highly specific for SLC26A4 (PP4; PMID: 14679580). However, the other variant in SLC26A4 harbored by this individual was not identified (PM3 not met). The REVEL computational prediction analysis tool produced a score of 0.954, which is above the threshold necessary to apply PP3; however, this information is not predictive of pathogenicity on its own (PP3). A different likely pathogenic missense variant (p.Gln421Pro) has been previously identified at this codon of SLC26A4, which may indicate that this residue is critical to the function of the protein (PM5; ClinVar ID: 556159). In summary, this variant meets criteria to be classified as likely pathogenic for autosomal recessive Pendred syndrome. ACMG/AMP Criteria applied, as specified by the Hearing Loss Expert Panel: PM2, PM5, PP3, PP4.
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
Natera, Inc.	RCV000673206	SCV001459923	likely pathogenic	Pendred syndrome	2020-09-16	no assertion criteria provided	clinical testing