Submissions for variant NM_012144.4(DNAI1):c.1948C>T (p.Arg650Cys)

gnomAD frequency: 0.00034  dbSNP: rs140820295

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000199193	SCV000255000	uncertain significance	Primary ciliary dyskinesia	2022-10-18	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 650 of the DNAI1 protein (p.Arg650Cys). This variant is present in population databases (rs140820295, gnomAD 0.06%). This variant has not been reported in the literature in individuals affected with DNAI1-related conditions. ClinVar contains an entry for this variant (Variation ID: 216677). 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) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on DNAI1 protein function. 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.
Counsyl	RCV000665810	SCV000789989	uncertain significance	Kartagener syndrome	2017-03-24	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV000665810	SCV001328077	uncertain significance	Kartagener syndrome	2018-01-12	criteria provided, single submitter	clinical testing	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease.
Genome-Nilou Lab	RCV000665810	SCV001786952	uncertain significance	Kartagener syndrome	2021-07-14	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV000199193	SCV002723998	uncertain significance	Primary ciliary dyskinesia	2024-10-02	criteria provided, single submitter	clinical testing	The p.R650C variant (also known as c.1948C>T), located in coding exon 19 of the DNAI1 gene, results from a C to T substitution at nucleotide position 1948. The arginine at codon 650 is replaced by cysteine, an amino acid with highly dissimilar properties. This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Johns Hopkins Genomics, Johns Hopkins University	RCV000665810	SCV004239043	uncertain significance	Kartagener syndrome	2023-12-01	criteria provided, single submitter	clinical testing	This DNAI1 missense variant (rs140820295) is rare (<0.1%) in a large population dataset (gnomAD v4.0.0: 698/1614192 total alleles; 0.04%; no homozygotes). It has been reported in ClinVar (Variation ID 216677), but has not been reported in the literature, to our knowledge. Two bioinformatic tools queried predict that this substitution would be deleterious, and the arginine residue at this position is evolutionarily conserved across most of the species assessed. We consider the clinical significance of c.1948C>T in DNAI1 to be uncertain at this time.
MAGI's Lab - Research, MAGI Group	RCV001283733	SCV001432676	uncertain significance	Male infertility	2020-07-01	no assertion criteria provided	provider interpretation
MAGI's Lab - Research, MAGI Group	RCV001327957	SCV001432735	uncertain significance	Infertility disorder		no assertion criteria provided	provider interpretation
Natera, Inc.	RCV000199193	SCV002085179	uncertain significance	Primary ciliary dyskinesia	2020-01-16	no assertion criteria provided	clinical testing