ClinVar Miner

Submissions for variant NM_024334.3(TMEM43):c.625T>G (p.Ser209Ala) (rs397517386)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Laboratory for Molecular Medicine, Partners HealthCare Personalized Medicine RCV000039390 SCV000063074 uncertain significance not specified 2011-11-23 criteria provided, single submitter clinical testing Variant classified as Uncertain Significance - Favor Benign. The Ser209Ala varia nt (TMEM43) has not been previously reported but has been identified by our labo ratory in 1 individual with DCM (this individual carried 3 additional variants o f unknown significance). Serine (Ser) at position 209 not conserved in mammals a nd some lower species, suggesting that a change may be tolerated. Computational tools (AlignGVGD, PolyPhen2, SIFT) also predict that a change to alanine (Ala) i s not likely to impact the protein, though their accuracy. Although this data su pports that the Ser209Ala variant may be likely benign, additional studies are n eeded to further assess its clinical significance.
GeneDx RCV000766713 SCV000529529 uncertain significance not provided 2016-07-06 criteria provided, single submitter clinical testing A variant of uncertain significance has been identified in the TMEM43 gene. The S209A variant has been reported in a patient with dilated cardiomyopathy (DCM); however, this patient also harbored variants in other cardiomyopathy-related genes (Pugh et al., 2014). Furthermore, the S209A variant has been classified as a variant of uncertain significance by another clinical laboratory in ClinVar (SCV000063074.5; Landrum et al., 2016). The S209A variant was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. The S209A variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. However, this substitution occurs at a position that is not conserved across species and in silico analysis predicts this variant likely does not alter the protein structure/function.Therefore, based on the currently available information, it is unclear whether this variant is pathogenic or rare benign.

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