Submissions for variant NM_001039876.3(SYNE4):c.559C>T (p.Arg187Ter)

gnomAD frequency: 0.00004  dbSNP: rs750797779

Total submissions: 3

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000213729	SCV000271268	likely pathogenic	Rare genetic deafness	2015-11-24	criteria provided, single submitter	clinical testing	The p.Arg187X variant in SYNE4 has not been previously reported in individuals w ith hearing loss, but has been identified in 1/3426 of Finnish chromosomes by th e Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.org). Although this variant has been seen in the general population, its frequency is low enoug h to be consistent with a recessive carrier frequency. This nonsense variant lea ds to a premature termination codon at position 187, which is predicted to lead to a truncated or absent protein. Loss of function of the SYNE4 gene has been as sociated with autosomal recessive hearing loss, based on a report describing two probands with hearing loss who had a homozygous frameshift variant in SYNE4, wh ich segregated in 4 affected family members, and a knock-out mouse model that al so displayed hearing loss (Horn 2013). In summary, although additional studies a re required to fully establish the association between loss of function variants in SYNE4 and autosomal recessive sensorineural hearing loss, based on the avail able data the p.Arg187X variant is likely pathogenic.
GeneDx	RCV000760544	SCV000890435	likely pathogenic	not provided	2021-07-08	criteria provided, single submitter	clinical testing	Observed in the heterozygous state in a family with autosomal dominant hearing loss who had a disease-causing variant in the TBC1D24 gene (Parzefall et al., 2020); Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; This variant is associated with the following publications: (PMID: 33281559)
Invitae	RCV000760544	SCV003521542	pathogenic	not provided	2023-11-01	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Arg187*) in the SYNE4 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in SYNE4 are known to be pathogenic (PMID: 23348741, 28958982). This variant is present in population databases (rs750797779, gnomAD 0.01%). This variant has not been reported in the literature in individuals affected with SYNE4-related conditions. ClinVar contains an entry for this variant (Variation ID: 228293). For these reasons, this variant has been classified as Pathogenic.