Submissions for variant NM_001369.3(DNAH5):c.10815del (p.Pro3606fs)

gnomAD frequency: 0.00021  dbSNP: rs397515540

Total submissions: 21

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000206560	SCV000261040	pathogenic	Primary ciliary dyskinesia	2024-10-25	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Pro3606Hisfs*23) 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 (rs397515540, gnomAD 0.03%), including at least one homozygous and/or hemizygous individual. This premature translational stop signal has been observed in individual(s) with primary ciliary dyskinesia (PMID: 16627867, 22416021, 23477994, 24498942). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 65636). For these reasons, this variant has been classified as Pathogenic.
Eurofins Ntd Llc (ga)	RCV000724843	SCV000700856	pathogenic	not provided	2017-01-03	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV000055849	SCV000915114	pathogenic	Primary ciliary dyskinesia 3	2016-10-17	criteria provided, single submitter	clinical testing	The DNAH5 c.10815delT (p.Pro3606HisfsTer23) variant results in a frameshift and is predicted to result in premature termination of the protein. The p.Pro3606HisfsTer23 variant has been reported in a total of 17 individuals with primary ciliary dyskinesia, including in two in a homozygous state and in 15 in a compound heterozygous state (Hornef et al. 2006; Djakow et al. 2012; Ferkol et al. 2013; Kim et al. 2014; Raidt et al. 2014). The p.Pro3606HisfsTer23 variant was found to segregate with disease where familial DNA was available, and haplotype analysis revealed this variant is a founder mutation (Hornef et al. 2006). The p.Pro3606HisfsTer23 variant was absent from 70 controls and is reported at a frequency of 0.00024 in the European (non-Finnish) population of the Exome Aggregation Consortium. Based on the evidence and potential impact of frameshift variants, the p.Pro3606HisfsTer23 variant is classified as pathogenic for primary ciliary dyskinesia. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population.
GeneDx	RCV000724843	SCV001168574	pathogenic	not provided	2022-02-20	criteria provided, single submitter	clinical testing	Frameshift variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; This variant is associated with the following publications: (PMID: 24498942, 16627867, 20301301, 28832562, 28991257, 23477994, 22416021, 29453417, 25186273, 31772028, 31879361, 31980526, 32111882, 31589614, 33726816)
Centre for Genomic and Experimental Medicine, University of Edinburgh	RCV000206560	SCV001334258	pathogenic	Primary ciliary dyskinesia	2020-04-01	criteria provided, single submitter	research
HudsonAlpha Institute for Biotechnology, HudsonAlpha Institute for Biotechnology	RCV000055849	SCV001364290	pathogenic	Primary ciliary dyskinesia 3	2020-03-26	criteria provided, single submitter	research	ACMG codes: PVS1, PM3, PP4, PP5
Revvity Omics, Revvity	RCV000055849	SCV002021713	pathogenic	Primary ciliary dyskinesia 3	2020-02-19	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV000724843	SCV002062574	pathogenic	not provided	2021-10-01	criteria provided, single submitter	clinical testing
Genetics and Molecular Pathology, SA Pathology	RCV000055849	SCV002556490	pathogenic	Primary ciliary dyskinesia 3	2020-05-13	criteria provided, single submitter	clinical testing	PVS1, PM3, PP5
Ambry Genetics	RCV000206560	SCV002729153	pathogenic	Primary ciliary dyskinesia	2021-12-06	criteria provided, single submitter	clinical testing	The c.10815delT pathogenic mutation, located in coding exon 63 of the DNAH5 gene, results from a deletion of one nucleotide at nucleotide position 10815, causing a translational frameshift with a predicted alternate stop codon (p.P3606Hfs*23). In one study, this mutation was seen in 7 of 134 (5.2%) primary ciliary dyskinesia (PCD) families, with a particularly high prevalence in individuals with PCD from the United States (Hornef N et al. Am. J. Respir. Crit. Care Med., 2006 Jul;174:120-6). In addition to the clinical data presented in the literature, this alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. As such, this alteration is interpreted as a disease-causing mutation.
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	RCV000055849	SCV002767601	pathogenic	Primary ciliary dyskinesia 3	2022-02-02	criteria provided, single submitter	clinical testing	Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with primary ciliary dyskinesia 3, with or without situs inversus (PCD; MIM#608644). (I) 0106 - This gene is associated with autosomal recessive disease. (I) 0201 - Variant is predicted to cause nonsense-mediated decay (NMD) and loss of protein (premature termination codon is located at least 54 nucleotides upstream of the final exon-exon junction). (SP) 0251 - This variant is heterozygous. (I) 0304 - Variant is present in gnomAD <0.01 for a recessive condition (v2: 45 heterozygotes, 1 homozygote). (SP) 0701 - Other NMD variants comparable to the one identified in this case have very strong previous evidence for pathogenicity (ClinVar, DECIPHER). (SP) 0801 - This variant has very strong previous evidence of pathogenicity in unrelated individuals. It has been reported in multiple families with primary ciliary dyskinesia (ClinVar, LOVD, PMIDs: 29363216, 16627867, 23477994). (SP) 1205 - This variant has been shown to be maternally inherited (by segregation analysis). (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign
Fulgent Genetics, Fulgent Genetics	RCV000055849	SCV002815495	pathogenic	Primary ciliary dyskinesia 3	2024-04-23	criteria provided, single submitter	clinical testing
Johns Hopkins Genomics, Johns Hopkins University	RCV000055849	SCV003839121	pathogenic	Primary ciliary dyskinesia 3	2022-12-06	criteria provided, single submitter	clinical testing	c.10815delT in DNAH5 has been identified in multiple unrelated individuals as well as families with primary ciliary dyskinesia and is a known North American founder mutation. This frameshift variant (rs397515540) has been reported in ClinVar (Variation ID 65636) and is rare (<0.1%) in a large population dataset (gnomAD v2.1.1: 47/282304 total alleles; 0.0167%; 1 homozygote). This frameshift variant results in a premature stop codon in exon 64 of 79, likely leading to nonsense-mediated decay and lack of protein production. We consider c.10815delT; p.Pro3606fs in DNAH5 to be pathogenic.
Institute Of Molecular Biology And Genetics, Federal Almazov National Medical Research Centre	RCV000206560	SCV004176738	pathogenic	Primary ciliary dyskinesia	2023-12-11	criteria provided, single submitter	clinical testing	ACMG: PVS1, PM2, PM3, PP5
Molecular Genetics, Royal Melbourne Hospital	RCV000206560	SCV004812509	pathogenic	Primary ciliary dyskinesia	2024-02-05	criteria provided, single submitter	clinical testing	This sequence change in DNAH5 is a frameshift variant predicted to cause a premature stop codon, p.(Pro3606Hisfs*23), in biologically relevant exon 64/79 leading to nonsense-mediated decay in a gene in which loss of function is an established disease mechanism. The highest population minor allele frequency in the population database gnomAD v4.0 is 0.05% (638/1,179,900 alleles) in the European (non-Finnish) population. This variant is a North American founder mutation that has been detected in the homozygous and compound heterozygous state in multiple individuals with primary ciliary dyskinesia (PCD), confirmed in trans in at least one individual (PMID: 16627867, 29363216). It segregates with PCD in at least one family (PMID: 16627867). Based on the classification scheme RMH Modified ACMG/AMP Guidelines v1.6.1, this variant is classified as PATHOGENIC. Following criteria are met: PVS1, PM3_VeryStrong, PP1.
Clinical Genetics Laboratory, Skane University Hospital Lund	RCV000724843	SCV005196649	pathogenic	not provided	2022-05-27	criteria provided, single submitter	clinical testing
GeneReviews	RCV000055849	SCV000086845	not provided	Primary ciliary dyskinesia 3		no assertion provided	literature only
Natera, Inc.	RCV000206560	SCV001452261	pathogenic	Primary ciliary dyskinesia	2020-09-16	no assertion criteria provided	clinical testing
Genomics England Pilot Project, Genomics England	RCV000055849	SCV001760150	likely pathogenic	Primary ciliary dyskinesia 3		no assertion criteria provided	clinical testing
OMIM	RCV000055849	SCV001768711	pathogenic	Primary ciliary dyskinesia 3	2006-07-15	no assertion criteria provided	literature only
Yale Center for Mendelian Genomics, Yale University	RCV000206560	SCV002106440	likely pathogenic	Primary ciliary dyskinesia	2018-08-01	no assertion criteria provided	literature only