Submissions for variant NM_000441.2(SLC26A4):c.556G>T (p.Val186Phe)

gnomAD frequency: 0.00002  dbSNP: rs760040670

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Counsyl	RCV000672704	SCV000797838	uncertain significance	Pendred syndrome	2018-02-13	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001731878	SCV001983468	uncertain significance	not specified	2021-09-15	criteria provided, single submitter	clinical testing	Variant summary: SLC26A4 c.556G>T (p.Val186Phe) results in a non-conservative amino acid change located in the SLC26A/SulP transporter domain 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 8e-06 in 251458 control chromosomes. c.556G>T has been reported in the literature a family affected with hearing loss and enlargement of the vestibular aqueduct (Muskett_2016). In this family, two affected individuals carried the variant along with a second mutation, while one unaffected family member also carried the variant of interest along with a second mutation. In experimental studies, the variant failed to traffic to the plasma membrane of COS-7 cells and exhibited minimal or undetectable anion transport activity in Xenopus oocytes as measured by either unidirectional 36Cl- influx or by 36Cl- efflux under conditions of Cl-/HCO3- exchange or Cl-/I- exchange (Muskett_2016). One clinical diagnostic laboratory has submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation and classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as VUS-possibly pathogenic.
Genome-Nilou Lab	RCV001004627	SCV002027000	uncertain significance	Autosomal recessive nonsyndromic hearing loss 4	2021-09-05	criteria provided, single submitter	clinical testing
Genome-Nilou Lab	RCV000672704	SCV002027001	uncertain significance	Pendred syndrome	2021-09-05	criteria provided, single submitter	clinical testing
Genetic Services Laboratory, University of Chicago	RCV001816678	SCV002064380	likely pathogenic	not provided	2018-03-30	criteria provided, single submitter	clinical testing
National Institute of Sensory Organs, National Hospital Organization Tokyo Medical Center	RCV001004627	SCV000994871	affects	Autosomal recessive nonsyndromic hearing loss 4	2019-08-20	no assertion criteria provided	literature only	in vitro experiment