ClinVar Miner

Submissions for variant NM_001128849.2(SMARCA4):c.778A>C (p.Met260Leu) (rs1064795842)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000486463 SCV000572030 uncertain significance not provided 2016-10-17 criteria provided, single submitter clinical testing This variant is denoted SMARCA4 c.778A>C at the cDNA level, p.Met260Leu (M260L) at the protein level, and results in the change of a Methionine to a Leucine (ATG>CTG). This variant has not, to our knowledge, been published in the literature as pathogenic or benign. SMARCA4 Met260Leu was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, suggesting it is not a common benign variant in these populations. Since Methionine and Leucine share similar properties, this is considered a conservative amino acid substitution. SMARCA4 Met260Leu occurs at a position that is conserved across species and is located in the region of interaction with SS18L1/CREST (UniProt). In silico analyses are inconsistent regarding the effect this variant may have on protein structure and function. Based on currently available evidence, it is unclear whether SMARCA4 Met260Leu is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Invitae RCV000550365 SCV000648173 uncertain significance Rhabdoid tumor predisposition syndrome 2 2019-11-01 criteria provided, single submitter clinical testing This sequence change replaces methionine with leucine at codon 260 of the SMARCA4 protein (p.Met260Leu). The methionine residue is highly conserved and there is a small physicochemical difference between methionine and leucine. This variant is not present in population databases (ExAC no frequency). This variant has not been reported in the literature in individuals with SMARCA4-related disease. ClinVar contains an entry for this variant (Variation ID: 422533). 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: "Benign"; Align-GVGD: "Class C0"). 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.
Fulgent Genetics,Fulgent Genetics RCV000764173 SCV000895175 uncertain significance Rhabdoid tumor predisposition syndrome 2; Mental retardation, autosomal dominant 16 2018-10-31 criteria provided, single submitter clinical testing
CeGaT Praxis fuer Humangenetik Tuebingen RCV000486463 SCV001151643 uncertain significance not provided 2018-03-01 criteria provided, single submitter clinical testing
Ambry Genetics RCV001026810 SCV001189265 uncertain significance Hereditary cancer-predisposing syndrome 2019-02-11 criteria provided, single submitter clinical testing Insufficient or conflicting evidence;Rarity in general population databases (dbsnp, esp, 1000 genomes)

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