Submissions for variant NM_001277115.2(DNAH11):c.4879C>T (p.Arg1627Cys)

gnomAD frequency: 0.00001  dbSNP: rs727502967

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000150435	SCV000197619	uncertain significance	not specified	2013-09-27	criteria provided, single submitter	clinical testing	The Arg1627Cys variant in DNAH11 has not been previously reported in individuals with lung disease or in large population studies. This residue is conserved in evolution and computational analyses (biochemical amino acid properties, AlignGV GD, PolyPhen2, and SIFT) predict that this variant will impact the normal functi on of the protein. In summary, this information is insufficient to establish the the clinical significance of the Arg1627Cys variant.
Invitae	RCV000556593	SCV000624133	uncertain significance	Primary ciliary dyskinesia	2022-08-15	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 1627 of the DNAH11 protein (p.Arg1627Cys). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This missense change has been observed in individual(s) with heterotaxy and primary ciliary dyskinesia (Invitae). ClinVar contains an entry for this variant (Variation ID: 163104). 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 DNAH11 protein function. This variant disrupts the p.Arg1627 amino acid residue in DNAH11. Other variant(s) that disrupt this residue have been observed in individuals with DNAH11-related conditions (PMID: 31772028; Invitae), which suggests that this may be a clinically significant amino acid residue. 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.
Johns Hopkins Genomics, Johns Hopkins University	RCV001263479	SCV001441560	uncertain significance	Primary ciliary dyskinesia 7	2020-10-20	criteria provided, single submitter	clinical testing	This DNAH11 variant (rs727502967) is rare (<0.1%) in a large population dataset (gnomAD: 3/280426 total alleles; 0.001%; no homozygotes) and has not been reported in ClinVar nor the literature, to our knowledge. Two bioinformatic tools queried predict that this substitution would be damaging, and the arginine residue at this position is highly evolutionarily conserved across most species assessed. Due to insufficient evidence that this variant is deleterious, we consider the clinical significance of c.4879C>T to be uncertain at this time.
Ambry Genetics	RCV000556593	SCV002634967	pathogenic	Primary ciliary dyskinesia	2021-08-26	criteria provided, single submitter	clinical testing	The p.R1627C pathogenic mutation (also known as c.4879C>T), located in coding exon 28 of the DNAH11 gene, results from a C to T substitution at nucleotide position 4879. The arginine at codon 1627 is replaced by cysteine, an amino acid with highly dissimilar properties. This mutation has been detected in multiple individuals with a clinical diagnosis or suspicion of primary ciliary dyskinesia, who have another pathogenic mutation in DNAH11 (internal Ambry data). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation.