ClinVar Miner

Submissions for variant NM_001082486.2(ACD):c.645G>A (p.Thr215=)

gnomAD frequency: 0.00001  dbSNP: rs571116752
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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Labcorp Genetics (formerly Invitae), Labcorp RCV000803286 SCV000943149 uncertain significance Dyskeratosis congenita, autosomal dominant 6 2023-12-14 criteria provided, single submitter clinical testing This sequence change affects codon 301 of the ACD mRNA. It is a 'silent' change, meaning that it does not change the encoded amino acid sequence of the ACD protein. This variant also falls at the last nucleotide of exon 7, which is part of the consensus splice site for this exon. This variant is present in population databases (rs571116752, gnomAD 0.05%). This variant has not been reported in the literature in individuals affected with ACD-related conditions. ClinVar contains an entry for this variant (Variation ID: 648536). Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. 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.
Ambry Genetics RCV002534740 SCV003560999 uncertain significance Inborn genetic diseases 2021-07-01 criteria provided, single submitter clinical testing The c.903G>A (p.T301T) alteration is located in exon 7 (coding exon 7) of the ACD gene. This alteration consists of a G to A substitution at nucleotide position 903. This nucleotide substitution does not change the amino acid at codon 301. However, this change occurs in the last nucleotide of Exon 7 (c.752_903) which makes it likely to have some effect on normal mRNA splicing. Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear.
Neuberg Centre For Genomic Medicine, NCGM RCV000803286 SCV005061098 uncertain significance Dyskeratosis congenita, autosomal dominant 6 criteria provided, single submitter clinical testing The observed synonymous variant c.645G>A (p.Thr215) in the ACD gene has not been reported previously as a pathogenic variant nor as a benign variant, to our knowledge. This p.Thr215 type of mutation causes no change in the protein that is produced, which is why it's considered as synonymous mutation. This variant has been reported to the ClinVar database as Uncertain significance. This variant is reported with the allele frequency 0.0004% in the gnomAD Exomes. It is predicted to be damaging as per SpliceAI prediction tool. For these reasons, this variant has been classified as uncertain significance.

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