Submissions for variant NM_001039876.3(SYNE4):c.699G>A (p.Trp233Ter)

gnomAD frequency: 0.00066  dbSNP: rs200484521

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000760529	SCV000890420	pathogenic	not provided	2024-08-06	criteria provided, single submitter	clinical testing	Observed with a pathogenic variant on the opposite allele (in trans) and with a pathogenic variant (phase unknown) in multiple patients referred for genetic testing at GeneDx; 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; Has not been previously published as pathogenic or benign in association with hearing loss to our knowledge; This variant is associated with the following publications: (PMID: 23348741, 29245897, 33057194, 35982159)
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV001801527	SCV002049802	likely pathogenic	Autosomal recessive nonsyndromic hearing loss 76	2021-11-30	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV000760529	SCV002132568	pathogenic	not provided	2024-12-19	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Trp233*) 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 (rs200484521, gnomAD 0.06%). 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: 228294). For these reasons, this variant has been classified as Pathogenic.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV002271467	SCV002556240	pathogenic	Nonsyndromic genetic hearing loss	2024-01-04	criteria provided, single submitter	clinical testing	Variant summary: SYNE4 c.699G>A (p.Trp233X) results in a premature termination codon and is predicted to cause absence of the protein due to nonsense mediated decay, a commonly known mechanism for disease. The variant allele was found at a frequency of 0.00079 in 1607538 control chromosomes, predominantly at a frequency of 0.001 within the Non-Finnish European subpopulation in the gnomAD database (v4). This frequency is not higher than estimated for a pathogenic variant in SYNE4 causing Nonsyndromic Hearing Loss And Deafness, Type 76 (0.001 vs 0.0011), allowing no strong conclusion about variant significance. To our knowledge, no occurrence of c.699G>A in individuals affected with Nonsyndromic Hearing Loss And Deafness and no experimental evidence demonstrating its impact on protein function have been reported. ClinVar contains an entry for this variant (Variation ID: 228294). Based on the evidence outlined above, the variant was classified as pathogenic.
Fulgent Genetics, Fulgent Genetics	RCV001801527	SCV005647427	likely pathogenic	Autosomal recessive nonsyndromic hearing loss 76	2024-01-25	criteria provided, single submitter	clinical testing
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000217413	SCV000271269	uncertain significance	not specified	2020-01-07	flagged submission	clinical testing	proposed classification - variant undergoing re-assessment, contact laboratory
PreventionGenetics, part of Exact Sciences	RCV003417771	SCV004118330	likely pathogenic	SYNE4-related disorder	2024-09-18	no assertion criteria provided	clinical testing	The SYNE4 c.699G>A variant is predicted to result in premature protein termination (p.Trp233*). At PreventionGenetics, this variant has been observed in the homozygous state or heterozygous state along with a likely pathogenic variant in four individuals undergoing testing for hearing loss from three apparently unrelated families (internal data). This variant has also been reported in the heterozygous state in one individual with a developmental disorder, although conclusive evidence of pathogenicity was not presented (Table S1, Kaplanis et al. 2020. PubMed ID: 33057194; Supplementary Data 3, Zhou et al. 2022. PubMed ID: 35982159). This variant is reported in 0.064% of alleles in individuals of European (Non-Finnish) descent in gnomAD. In relation to autosomal recessive hearing loss, this variant is interpreted as likely pathogenic.