ClinVar Miner

Submissions for variant NM_002968.2(SALL1):c.3414_3415del (p.Cys1139fs) (rs1064793257)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000486755 SCV000565515 pathogenic not provided 2017-12-28 criteria provided, single submitter clinical testing The c.3414_3415delAT pathogenic variant in the SALL1 gene has been reported previously in multiple individuals with features of Townes-Brocks syndrome, including one patient with isolated renal hypoplasia (Weber et al., 2006; Furniss et al., 2007; Botzenhart et al., 2007; Lawrence et al., 2013). The c.3414_3415delAT variant causes a frameshift starting with codon Cysteine 1139, changes this amino acid to a Tryptophan residue, and creates a premature Stop codon at position 35 of the new reading frame, denoted p.Cys1139TrpfsX35. This variant is predicted to cause loss of normal protein function through protein truncation. The c.3414_3415delAT variant has been shown to be associated with reduced levels of cDNA in fibroblasts as compared to wild type but similar levels when treated with an inhibitor of nonsense-mediated mRNA decay (NMD), suggesting that the variant transcript undergoes NMD (Furniss et al., 2007). The c.3414_3415delAT variant is not observed in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). We interpret c.3414_3415delAT as a pathogenic variant.
Invitae RCV000526857 SCV000630911 pathogenic Townes syndrome 2017-05-16 criteria provided, single submitter clinical testing This sequence change deletes 2 nucleotide from exon 2 of the SALL1 mRNA (c.3414_3415delAT), causing a frameshift at codon 1139. This creates a premature translational stop signal in the last exon of the SALL1 mRNA (p.Cys1139Trpfs*35). While this is not anticipated to result in nonsense-mediated decay, it is expected to disrupt the last 186 amino acids of the SALL1 protein. This variant is not present in population databases (ExAC no frequency). This particular variant has been reported in the literature in individuals affected with renal hypoplasia, congenital limb malformation, and Townes-Brocks syndrome (PMID: 16971658, 23894113, 19429598, 18000979). It has also been reported to segregate with disease in 2 families affected with Townes-Brocks syndrome (PMID: 23894113, 17221874). For these reasons, this variant has been classified as Pathogenic.

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