Submissions for variant NM_000441.2(SLC26A4):c.347G>T (p.Gly116Val)

dbSNP: rs2129311246

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV002030086	SCV002116953	likely pathogenic	not provided	2021-08-25	criteria provided, single submitter	clinical testing	Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt SLC26A4 protein function. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. This variant disrupts the p.Gly116 amino acid residue in SLC26A4. Other variant(s) that disrupt this residue have been observed in individuals with SLC26A4-related conditions (PMID: 25372295, 29871349, 32279305), which suggests that this may be a clinically significant amino acid residue. This variant has been observed in individual(s) with deafness (PMID: 22903915). This variant is not present in population databases (ExAC no frequency). This sequence change replaces glycine with valine at codon 116 of the SLC26A4 protein (p.Gly116Val). The glycine residue is highly conserved and there is a moderate physicochemical difference between glycine and valine.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV004526869	SCV005039888	likely pathogenic	Pendred syndrome	2024-03-15	criteria provided, single submitter	clinical testing	Variant summary: SLC26A4 c.347G>T (p.Gly116Val) results in a non-conservative amino acid change located in the SLC26A/SulP transporter domain (IPR011547) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 251428 control chromosomes (gnomAD). c.347G>T has been reported in the literature in at least two homozygous individuals affected with nonsyndromic hearing loss (e.g., Babanejad_2012, Sloan-Heggen_2015). These data indicate that the variant is likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 22903915, 26445815). ClinVar contains an entry for this variant (Variation ID: 1346580). Based on the evidence outlined above, the variant was classified as likely pathogenic.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV004542138	SCV005040773	likely pathogenic	RASopathy	2024-03-15	criteria provided, single submitter	clinical testing	Variant summary: CBL c.347G>T (p.Arg116Met) results in a non-conservative amino acid change located in the N-terminal helical domain (IPR003153) and PTB domain (IPR024159) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 4e-06 in 251424 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. To our knowledge, no occurrence of c.347G>T in individuals affected with Noonan Syndrome And Related Conditions and no experimental evidence demonstrating its impact on protein function have been reported. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014. Based on the evidence outlined above, the variant was classified as uncertain significance.
Fulgent Genetics, Fulgent Genetics	RCV005040413	SCV005674160	likely pathogenic	Autosomal recessive nonsyndromic hearing loss 4; Pendred syndrome	2024-03-21	criteria provided, single submitter	clinical testing