ClinVar Miner

Submissions for variant NM_000489.5(ATRX):c.4070A>G (p.Lys1357Arg) (rs1064796812)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Geisinger Autism and Developmental Medicine Institute,Geisinger Health System RCV000678264 SCV000804319 uncertain significance Acquired hemoglobin H disease; ATR-X syndrome; Mental retardation-hypotonic facies syndrome X-linked, 1 2017-03-13 criteria provided, single submitter provider interpretation This 4 year old male has a history of autism spectrum disorder, speech and language disorder, and mild hypotonia. The maternally inherited ATRX variant (c.4070A>G) is absent from population databases (ExAC and gnomAD). Computational models are inconsistent.
GeneDx RCV000481959 SCV000573909 uncertain significance not provided 2017-03-03 criteria provided, single submitter clinical testing The K1357R variant in the ATRX gene has not been reported previously as a pathogenic variant, nor as a benign variant, to our knowledge. The K1357R variant is not observed in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). The K1357R variant is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties. This substitution occurs at a position that is not conserved. In silico analysis is inconsistent in its predictions as to whether or not the variant is damaging to the protein structure/function. We interpret K1357R as a variant of uncertain significance.
GenomeConnect, ClinGen RCV000509350 SCV000607171 not provided ATRX-Related Disorder no assertion provided phenotyping only GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical significance of the variant.
Invitae RCV000698093 SCV000826736 uncertain significance ATR-X syndrome 2018-04-25 criteria provided, single submitter clinical testing This sequence change replaces lysine with arginine at codon 1357 of the ATRX protein (p.Lys1357Arg). The lysine residue is moderately conserved and there is a small physicochemical difference between lysine and arginine. This variant is not present in population databases (ExAC no frequency). This variant has not been reported in the literature in individuals with ATRX-related disease. ClinVar contains an entry for this variant (Variation ID: 424128). 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, suggesting that this missense change does not adversely affect protein function. These predictions have not been confirmed by published functional studies and their clinical significance is uncertain. 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.

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