ClinVar Miner

Submissions for variant NM_000441.2(SLC26A4):c.1001G>T (p.Gly334Val) (rs146281367)

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Total submissions: 8
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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 Deafness, autosomal recessive 4, with enlarged vestibular aqueduct; 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.
Invitae RCV001381509 SCV001579941 pathogenic not provided 2020-05-25 criteria provided, single submitter clinical testing This sequence change replaces glycine with valine at codon 334 of the SLC26A4 protein (p.Gly334Val). The glycine residue is highly conserved and there is a moderate physicochemical difference between glycine and valine. This variant also falls at the last nucleotide of exon 8 of the SLC26A4 coding sequence, which is part of the consensus splice site for this exon. This variant is present in population databases (rs146281367, ExAC 0.006%). This variant has been observed in individual(s) with SLC26A4-related conditions (PMID: 16460646, 28964290, 18813951). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 189039). This variant has been reported to affect SLC26A4 protein function (PMID: 22116360). Nucleotide substitutions within the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Experimental studies have shown that this variant disrupts mRNA splicing (PMID: 16460646). For these reasons, this variant has been classified as Pathogenic.
GeneDx RCV001381509 SCV001872679 pathogenic not provided 2021-07-19 criteria provided, single submitter clinical testing This variant is demonstrated to create a cryptic splice site and result in loss-of-function (Walsh et al., 2006); Not observed at a significant frequency in large population cohorts (Lek et al., 2016); This variant is associated with the following publications: (PMID: 16460646, 22116360, 27535533, 28964290, 27771369, 18813951, 31599023, 31033086, 29372807)
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 Deafness, autosomal recessive 4, with enlarged vestibular aqueduct 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 Deafness, autosomal recessive no assertion criteria provided research

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