Submissions for variant NM_000441.2(SLC26A4):c.1001G>T (p.Gly334Val)

dbSNP: rs146281367

Total submissions: 13

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Counsyl	RCV000169430	SCV000220842	likely pathogenic	Pendred syndrome	2014-10-28	criteria provided, single submitter	literature only
Fulgent Genetics, Fulgent Genetics	RCV000763146	SCV000893727	likely pathogenic	Autosomal recessive nonsyndromic hearing loss 4; Pendred syndrome	2018-10-31	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000169430	SCV001572421	pathogenic	Pendred syndrome	2021-04-09	criteria provided, single submitter	clinical testing	Variant summary: SLC26A4 c.1001G>T (p.Gly334Val) 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. Several computational tools predict a significant impact on normal splicing: Three predict the variant weakens a 5' donor site, with two of them also predicting that it creates a new cryptic exonic 5 donor site. Experimental evidence supports these predictions demonstrating the variant affects mRNA splicing leading to inclusion of intronic material and introduction of a premature stop codon (e.g. Walsh_2006, Wasano_2020). The variant allele was found at a frequency of 8e-06 in 250276 control chromosomes (gnomAD). c.1001G>T has been reported in the literature to segregate with disease in families with multiple homozygous individuals affected with Pendred Syndrome (e.g. Walsh_2006, Kahrizi_2009). These data indicate that the variant is very likely to be associated with disease. Experimental evidence evaluating an impact on protein function demonstrated the variant to impair ion transport activity (e.g. Dossena_2011, Wasano_2020). Two ClinVar submitters (evaluation after 2014) cite the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Labcorp Genetics (formerly Invitae), Labcorp	RCV001381509	SCV001579941	pathogenic	not provided	2024-01-22	criteria provided, single submitter	clinical testing	This sequence change replaces glycine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 334 of the SLC26A4 protein (p.Gly334Val). RNA analysis indicates that this missense change induces altered splicing and may result in an absent or disrupted protein product. This variant is present in population databases (rs146281367, gnomAD 0.003%). This missense change has been observed in individual(s) with SLC26A4-related conditions (PMID: 16460646, 18813951, 28964290). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 189039). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. Experimental studies have shown that this missense change affects SLC26A4 function (PMID: 22116360). Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Studies have shown that this missense change results in the inclusion of part of intron 8 and introduces a premature termination codon (PMID: 16460646). The resulting mRNA is expected to undergo nonsense-mediated decay. For these reasons, this variant has been classified as Pathogenic.
GeneDx	RCV001381509	SCV001872679	pathogenic	not provided	2024-11-13	criteria provided, single submitter	clinical testing	Demonstrated to create a cryptic splice site and result in loss-of-function (PMID: 16460646); Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 31599023, 29372807, 16460646, 31033086, 28964290, 18813951, 27771369, 32747562, 31589614, 22116360, 34426522, 36555390, 35982127, 39107234, Stepanova2022(article), 34632506, 33614372, 26445815, 38474007)
Genome-Nilou Lab	RCV000169430	SCV002026754	pathogenic	Pendred syndrome	2021-09-05	criteria provided, single submitter	clinical testing
King Laboratory, University of Washington	RCV001004633	SCV002059884	pathogenic	Autosomal recessive nonsyndromic hearing loss 4	2020-08-01	criteria provided, single submitter	research	SLC26A4 c.1001G>T, p.G334V is a founder allele in the Palestinian population. Analysis of patient-derived RNA indicates that the variant disrupts the donor splice of SLC26A4 exon 8, with two mutant messages: (1) loss of exon 8 (83bp) with stop at codon 311. (2) activation of a cryptic splice donor with insertion of 40 bp in exon 8 message and stop at codon 355. (Abu Rayyan 2020). The variant is homozygous in 23 children from 10 Palestinian families with severe to profound pre-lingual hearing loss (Abu Rayyan 2020). It is absent from 1300 Palestinian controls and present in 51/250276 alleles on gnomAD, all heterozygotes.
The Shared Resource Centre "Genome", Research Centre for Medical Genetics	RCV001004633	SCV002756425	pathogenic	Autosomal recessive nonsyndromic hearing loss 4	2022-11-10	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV001004633	SCV004201850	pathogenic	Autosomal recessive nonsyndromic hearing loss 4	2024-02-20	criteria provided, single submitter	clinical testing
Hereditary Research Laboratory, Bethlehem University	RCV000169430	SCV000538116	pathogenic	Pendred syndrome	2016-06-04	no assertion criteria provided	research	Severe to Profound SNHL
National Institute of Sensory Organs, National Hospital Organization Tokyo Medical Center	RCV001004633	SCV000994878	affects	Autosomal recessive nonsyndromic hearing loss 4	2019-08-20	no assertion criteria provided	literature only	in vitro experiment
University of Washington Center for Mendelian Genomics, University of Washington	RCV001291248	SCV001479673	likely pathogenic	Hearing loss, autosomal recessive		no assertion criteria provided	research
Natera, Inc.	RCV000169430	SCV002079984	pathogenic	Pendred syndrome	2020-12-16	no assertion criteria provided	clinical testing