ClinVar Miner

Submissions for variant NM_130468.4(CHST14):c.958C>T (p.Arg320Ter)

gnomAD frequency: 0.00001  dbSNP: rs1555410784
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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000498443 SCV000590701 likely pathogenic not provided 2019-11-21 criteria provided, single submitter clinical testing Has not been previously published as pathogenic or benign to our knowledge; Not observed at a significant frequency in large population cohorts (Lek et al., 2016); Nonsense variant in the C-terminus predicted to result in protein truncation, as the last 57 amino acids are lost; Other loss-of-function variants have been reported downstream of this variant in the Human Gene Mutation Database in association with mcEDS (Stenson et al., 2014)
Invitae RCV002524105 SCV003243450 uncertain significance Ehlers-Danlos syndrome, musculocontractural type 2022-04-30 criteria provided, single submitter clinical testing This sequence change creates a premature translational stop signal (p.Arg320*) in the CHST14 gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 57 amino acid(s) of the CHST14 protein. This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with CHST14-related conditions. ClinVar contains an entry for this variant (Variation ID: 432924). This variant disrupts the C-terminus of the CHST14 protein. Other variant(s) that disrupt this region (p.Trp327Cysfs*29) have been observed in individuals with CHST14-related conditions (PMID: 26373698). This suggests that this may be a clinically significant region of the protein. 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 RCV003302737 SCV004000759 likely pathogenic Cardiovascular phenotype 2023-05-15 criteria provided, single submitter clinical testing The p.R320* variant (also known as c.958C>T), located in coding exon 1 of the CHST14 gene, results from a C to T substitution at nucleotide position 958. This changes the amino acid from an arginine to a stop codon within coding exon 1. This alteration is not expected to trigger nonsense-mediated mRNA decay and only impacts the last 57 amino acids of the protein. However, premature stop codons are typically deleterious in nature and a significant portion of the protein is affected (Ambry internal data). This alteration has been reported in musculocontractural Ehlers-Danlos syndrome cohorts (Minatogawa M et al. J Med Genet, 2022 Sep;59:865-877; Zhou YY et al. Front Genet, 2022 Apr;13:853907). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). Based on the majority of available evidence to date, this variant is likely to be pathogenic.

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