Submissions for variant NM_002968.2(SALL1):c.3160C>T (p.Arg1054Ter) (rs864321635)

Total submissions: 2

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneReviews	RCV000203506	SCV000258634	pathogenic	Townes-Brocks syndrome 1	2016-01-14	no assertion criteria provided	literature only
Invitae	RCV000634152	SCV000755451	uncertain significance	Townes syndrome	2017-10-09	criteria provided, single submitter	clinical testing	This sequence change results in a premature translational stop signal in the SALL1 gene (p.Arg1054*). This variant is not present in population databases (ExAC no frequency). This variant has been reported to segregate with multiple congenital anomaly-mental retardation (MCA-MR) in a family (PMID: 23069192). In this family, two affected siblings were homozygous for this variant. Eleven heterozygous carriers from this family were clinically evaluated with emphasis on minor Townes-Brocks syndrome (TBS) features, and were all found to be unaffected. Another heterozygous carrier, who was not available for thorough clinical evaluation, was also reported to be healthy. However, this variant has also been observed in a different family, where the heterozygous proband and a heterozygous parent had clinical features suggestive of TBS (Invitae). ClinVar contains an entry for this variant (Variation ID: 219151). Experimental studies in fibroblasts from heterozygous carriers of this variant suggests that this premature translational stop signal leads to partial nonsense-mediated decay (PMID: 23069192). The clinical significance of these findings are unclear. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site, but this prediction has not been confirmed by published transcriptional studies. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.