ClinVar Miner

Submissions for variant NM_024334.2(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
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.
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.

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