Submissions for variant NM_005876.5(SPEG):c.4759G>A (p.Gly1587Arg)

gnomAD frequency: 0.00013  dbSNP: rs200114716

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Baylor Genetics	RCV001330138	SCV001521745	uncertain significance	Myopathy, centronuclear, 5	2019-03-07	criteria provided, single submitter	clinical testing	This variant was determined to be of uncertain significance according to ACMG Guidelines, 2015 [PMID:25741868].
Invitae	RCV001871809	SCV002133270	uncertain significance	not provided	2022-10-17	criteria provided, single submitter	clinical testing	This sequence change replaces glycine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 1587 of the SPEG protein (p.Gly1587Arg). This variant is present in population databases (rs200114716, gnomAD 0.02%). This variant has not been reported in the literature in individuals affected with SPEG-related conditions. ClinVar contains an entry for this variant (Variation ID: 1028952). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Tolerated"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0". The arginine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. 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.
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	RCV001330138	SCV002768491	uncertain significance	Myopathy, centronuclear, 5	2020-05-21	criteria provided, single submitter	clinical testing	A heterozygous missense variant was identified, NM_005876.4(SPEG):c.4759G>A in exon 21 of 41 of the SPEG gene (NB: this variant is non-coding in an alternative transcript). This substitution is predicted to create a major amino acid change from a glycine to an arginine at position 1587 of the protein; NP_005867.3(SPEG):p.(Gly1587Arg). The glycine at this position has very low conservation (100 vertebrates, UCSC), and is is not situated in a known functional domain. In silico software predicts this variant to be tolerated (Polyphen, SIFT, CADD, Mutation Taster). The variant is present in the gnomAD database at a global population frequency of 0.01% (36 heterozygotes, 0 homozygotes) with a European sub-population frequency of 0.025%. This variant has been previously reported unclassified in the SPEG Cardiomyopathy Database. Based on information available at the time of curation, this variant has been classified as a VUS with LOW CLINICAL RELEVANCE.
Revvity Omics, Revvity	RCV001330138	SCV003820013	uncertain significance	Myopathy, centronuclear, 5	2022-01-27	criteria provided, single submitter	clinical testing
GeneDx	RCV001871809	SCV003837056	uncertain significance	not provided	2022-09-01	criteria provided, single submitter	clinical testing	In silico analysis supports that this missense variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge
Ambry Genetics	RCV003284207	SCV003962895	uncertain significance	Inborn genetic diseases	2023-03-24	criteria provided, single submitter	clinical testing	The c.4759G>A (p.G1587R) alteration is located in exon 21 (coding exon 21) of the SPEG gene. This alteration results from a G to A substitution at nucleotide position 4759, causing the glycine (G) at amino acid position 1587 to be replaced by an arginine (R). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear.