Submissions for variant NM_012144.4(DNAI1):c.370C>T (p.Arg124Cys)

gnomAD frequency: 0.00053  dbSNP: rs116938457

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Eurofins Ntd Llc (ga)	RCV000178924	SCV000231104	uncertain significance	not provided	2014-09-05	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV000233417	SCV000289877	pathogenic	Primary ciliary dyskinesia	2024-01-27	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 124 of the DNAI1 protein (p.Arg124Cys). This variant is present in population databases (rs116938457, gnomAD 0.06%). This missense change has been observed in individual(s) with primary ciliary dyskinesia (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: 197793). 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. For these reasons, this variant has been classified as Pathogenic.
Illumina Laboratory Services, Illumina	RCV001095357	SCV000479741	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.
Ambry Genetics	RCV000233417	SCV002621356	uncertain significance	Primary ciliary dyskinesia	2023-12-13	criteria provided, single submitter	clinical testing	The p.R124C variant (also known as c.370C>T), located in coding exon 5 of the DNAI1 gene, results from a C to T substitution at nucleotide position 370. The arginine at codon 124 is replaced by cysteine, an amino acid with highly dissimilar properties. This amino acid position is well conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Mayo Clinic Laboratories, Mayo Clinic	RCV000178924	SCV005409601	uncertain significance	not provided	2024-09-05	criteria provided, single submitter	clinical testing	PP1, PM3_supporting, PS4_moderate
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	RCV000178924	SCV001741722	uncertain significance	not provided		no assertion criteria provided	clinical testing
Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	RCV000178924	SCV001798208	uncertain significance	not provided		no assertion criteria provided	clinical testing