Submissions for variant NM_001369.3(DNAH5):c.4348C>T (p.Gln1450Ter)

gnomAD frequency: 0.00001  dbSNP: rs771663107

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000814567	SCV000954980	pathogenic	Primary ciliary dyskinesia	2023-12-16	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Gln1450*) in the DNAH5 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in DNAH5 are known to be pathogenic (PMID: 11788826, 16627867). This variant is present in population databases (rs771663107, gnomAD 0.002%). This premature translational stop signal has been observed in individual(s) with primary ciliary dyskinesia (PMID: 19357118, 23477994). ClinVar contains an entry for this variant (Variation ID: 208992). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic.
Neuberg Centre For Genomic Medicine, NCGM	RCV000477807	SCV002073051	pathogenic	Primary ciliary dyskinesia 3		criteria provided, single submitter	clinical testing	The stop gained p.Q1450* in DNAH5 (NM_001369.3) has been previously reported in homozygous state in affected individuals including those of Amish origin (Ferkol TW et al; Strauss KA et al). The variant has been submitted to ClinVar as Pathogenic. Although the variant is present at 0.0004% in gnomAD Exomes, it has the flag "Failed Random Forest" and may not represent the true population frequency. The p.Q1450* variant is novel (not in any individuals) in 1000 Genomes. This variant is predicted to cause loss of normal protein function through protein truncation. Loss of function variants have been previously reported to be disease causing. For these reasons, this variant has been classified as Pathogenic.
Ambry Genetics	RCV000814567	SCV002632192	pathogenic	Primary ciliary dyskinesia	2014-08-08	criteria provided, single submitter	clinical testing	The p.Q1450* pathogenic mutation (also known as c.4348C>T) located in coding exon 27 of the DNAH5 gene, results from a C to T substitution at nucleotide position 4348. This changes the amino acid from a glutamine to a stop codon within coding exon 27. Eight members of a consanguineous Amish family from Pennsylvania who all had neonatal respiratory distress, situs inversus totalis, chronic pneumonia, or rhinosinusitis were found to be homozygous for this mutation. This paper also identified four additional affected individuals who were either homozygous or heterozygous (phase was confirmed trans through parental testing) for this mutation (Ferkol TW, et al. J. Pediatr. 2013 Aug; 163(2):383-7). Another study identified two affected individuals who each carried another mutation, Q3455H and E4133*, in conjunction with this mutation; however, phase was not specified (Failly M, et al. J. Med. Genet. 2009 Apr; 46(4):281-6). In addition to the clinical data presented in the literature, since premature stop codons are typically deleterious in nature, this alteration is interpreted as a disease-causing mutation (ACMG Recommendations for Standards for Interpretation and Reporting of Sequence Variations. Revision 2007. Genet Med. 2008;10:294).
Fulgent Genetics, Fulgent Genetics	RCV000477807	SCV002810547	pathogenic	Primary ciliary dyskinesia 3	2021-10-27	criteria provided, single submitter	clinical testing
GeneReviews	RCV000190910	SCV000245796	not provided	Kartagener syndrome		no assertion provided	literature only
Division of Human Genetics, Children's Hospital of Philadelphia	RCV000477807	SCV000536766	pathogenic	Primary ciliary dyskinesia 3	2016-04-27	no assertion criteria provided	research
Natera, Inc.	RCV000814567	SCV002080951	pathogenic	Primary ciliary dyskinesia	2021-01-19	no assertion criteria provided	clinical testing
Yale Center for Mendelian Genomics, Yale University	RCV000814567	SCV002106439	likely pathogenic	Primary ciliary dyskinesia	2018-08-01	no assertion criteria provided	literature only