Submissions for variant NM_014363.6(SACS):c.4612A>G (p.Ile1538Val) (rs544249449)

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Total submissions: 2

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Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Athena Diagnostics Inc	RCV000518100	SCV000614957	uncertain significance	not specified	2016-11-16	criteria provided, single submitter	clinical testing
Invitae	RCV000547323	SCV000629467	uncertain significance	Spastic paraplegia	2017-06-23	criteria provided, single submitter	clinical testing	This sequence change replaces isoleucine with valine at codon 1538 of the SACS protein (p.Ile1538Val). The isoleucine residue is highly conserved and there is a small physicochemical difference between isoleucine and valine. This variant is present in population databases (rs544249449, ExAC 0.02%). This variant has not been reported in the literature in individuals with a SACS-related disease. Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). 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, this variant has uncertain impact on SACS function. The available evidence is currently insufficient to determine its role in disease. Therefore, it has been classified as a Variant of Uncertain Significance.

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