ClinVar Miner

Submissions for variant NM_001082486.2(ACD):c.1213C>A (p.Pro405Thr)

gnomAD frequency: 0.00002  dbSNP: rs201441120
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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000225075 SCV001206229 uncertain significance Dyskeratosis congenita, autosomal dominant 6 2023-05-20 criteria provided, single submitter clinical testing 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. Experimental studies have shown that this missense change does not substantially affect ACD function (PMID: 25233904). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt ACD protein function. ClinVar contains an entry for this variant (Variation ID: 208984). This missense change has been observed in individual(s) with Hoyeraal-Hreidarsson syndrome (PMID: 25233904). This variant is present in population databases (rs201441120, gnomAD 0.01%). This sequence change replaces proline, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 491 of the ACD protein (p.Pro491Thr).
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital RCV002267926 SCV002551705 uncertain significance not specified 2024-02-06 criteria provided, single submitter clinical testing
Johns Hopkins Genomics, Johns Hopkins University RCV000225075 SCV002570293 uncertain significance Dyskeratosis congenita, autosomal dominant 6 2022-04-29 criteria provided, single submitter clinical testing ACD c.1213C>A has been previously identified in an individual with dyskeratosis congenita, autosomal recessive 7 who carried a second ACD variant on the opposite allele. This individual's healthy mother carried c.1213C>A in the heterozygous state and had normal telomere length. This variant has been reported in ClinVar (Variation ID: 208984) and is rare (<0.1%) in a large population dataset (gnomAD: 13/251316 total alleles; 0.005173%; no homozygotes). In vitro functional studies indicate that p.Pro405Thr may result in a modest decrease in binding between ACD and TIN2,however the clinical significance of this finding is uncertain. The proline residue at this position is evolutionarily conserved in most mammalian species assessed. We consider the clinical significance of ACD c.1213C>A to be uncertain at this time.
OMIM RCV000190905 SCV000245779 pathogenic Dyskeratosis congenita, autosomal recessive 7 2014-10-01 no assertion criteria provided literature only
GeneReviews RCV000225075 SCV000282032 not provided Dyskeratosis congenita, autosomal dominant 6 no assertion provided literature only

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