ClinVar Miner

Submissions for variant NM_012144.4(DNAI1):c.1543G>A (p.Gly515Ser)

gnomAD frequency: 0.00003  dbSNP: rs79833450
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Total submissions: 7
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000468431 SCV000553226 pathogenic Primary ciliary dyskinesia 2023-12-10 criteria provided, single submitter clinical testing This sequence change replaces glycine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 515 of the DNAI1 protein (p.Gly515Ser). This variant is present in population databases (rs79833450, gnomAD 0.009%). This missense change has been observed in individual(s) with clinical features of primary ciliary dyskinesia (PMID: 11231901, 21143860, 30868567; Invitae). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 5606). 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 DNAI1 protein function with a positive predictive value of 80%. For these reasons, this variant has been classified as Pathogenic.
Institute Of Human Genetics Munich, Klinikum Rechts Der Isar, Tu München RCV000005956 SCV001149762 pathogenic Kartagener syndrome 2018-07-19 criteria provided, single submitter clinical testing
Ambry Genetics RCV000468431 SCV002709301 pathogenic Primary ciliary dyskinesia 2014-07-09 criteria provided, single submitter clinical testing The p.G515S pathogenic mutation (also known as c.1543G>A), located in coding exon 16 of the DNAI1 gene, results from a G to A substitution at nucleotide position 1543. The glycine at codon 515 is replaced by serine. This pathogenic mutation was first described in two siblings with recurrent respiratory infections, immotile spermatozoa, and one sibling was confirmed to have absent or truncated outer dynein arms on electron microscopy; both siblings also carried the c.48+2dupT pathogenic mutation in trans (Guichard C et al. Am J Hum Genet. 2001;68(4):1030-5). This pathogenic mutation has also been described in a patient, who also carried the c.48+2dupT pathogenic mutation, with recurrent respiratory infetions, situs inversus, nasal polyps, but no outer dynein defects on electron microscopy; however, ex vivo cultures of the patient's epithelial airway found his cilia were immotile (Chhin B et al. PLoS Genet. 2009;5(3):e1000422). Based on the supporting evidence, p.G515S is interpreted as a disease-causing mutation.
Fulgent Genetics, Fulgent Genetics RCV000005956 SCV002811155 likely pathogenic Kartagener syndrome 2021-08-22 criteria provided, single submitter clinical testing
Preventiongenetics, part of Exact Sciences RCV003407285 SCV004109483 likely pathogenic DNAI1-related condition 2023-03-30 criteria provided, single submitter clinical testing The DNAI1 c.1543G>A variant is predicted to result in the amino acid substitution p.Gly515Ser. This variant has been reported in the compound heterozygous state with a second DNAI1 variant in individuals with Kartagener syndrome or primary ciliary dyskinesia (Guichard et al 2001. PubMed ID: 11231901; Chhin B et al 2009. PubMed ID: 19300481; Ziętkiewicz E et al 2010. PubMed ID: 21143860; Westphal DS et al 2019. PubMed ID: 30868567). This variant is reported in 0.0087% of alleles in individuals of Latino descent in gnomAD (http://gnomad.broadinstitute.org/variant/9-34513163-G-A). This variant is interpreted as likely pathogenic.
OMIM RCV000005956 SCV000026138 pathogenic Kartagener syndrome 2001-04-01 no assertion criteria provided literature only
Natera, Inc. RCV000468431 SCV001462306 likely pathogenic Primary ciliary dyskinesia 2020-09-16 no assertion criteria provided clinical testing

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