Submissions for variant NM_012472.6(DNAAF11):c.436G>C (p.Asp146His)

gnomAD frequency: 0.00011  dbSNP: rs200321595

Total submissions: 10

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000033020	SCV000772163	pathogenic	Primary ciliary dyskinesia 19	2024-11-27	criteria provided, single submitter	clinical testing	This sequence change replaces aspartic acid, which is acidic and polar, with histidine, which is basic and polar, at codon 146 of the LRRC6 protein (p.Asp146His). This variant is present in population databases (rs200321595, gnomAD 0.03%). This missense change has been observed in individual(s) with primary ciliary dyskinesia (PMID: 23122589, 23527195, 23891469). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 39798). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is expected to disrupt LRRC6 protein function with a positive predictive value of 80%. Experimental studies have shown that this missense change affects LRRC6 function (PMID: 23527195). For these reasons, this variant has been classified as Pathogenic.
Centre for Mendelian Genomics, University Medical Centre Ljubljana	RCV000033020	SCV001368647	pathogenic	Primary ciliary dyskinesia 19	2019-08-20	criteria provided, single submitter	clinical testing	This variant was classified as: Pathogenic. The following ACMG criteria were applied in classifying this variant: PS1,PS3,PM2,PP3.
Ambry Genetics	RCV002460894	SCV002755383	pathogenic	Primary ciliary dyskinesia	2023-09-01	criteria provided, single submitter	clinical testing	The p.D146H pathogenic mutation (also known as c.436G>C), located in coding exon 5 of the LRRC6 gene, results from a G to C substitution at nucleotide position 436. The aspartic acid at codon 146 is replaced by histidine, an amino acid with similar properties. This mutation was identified in the compound heterozygous state in two individuals with primary ciliary dyskinesia (PCD) and absent dynein arms (Kott E et al. Am. J. Hum. Genet., 2012 Nov;91:958-64; Zariwala MA et al. Am. J. Hum. Genet., 2013 Aug;93:336-45). It was also identified in the homozyogus state is 5 individuals with PCD from 2 unrelated families; all five individuals had absent dynein arms and three had situs abnormalities (Horani A et al. PLoS ONE, 2013 Mar;8:e59436). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation.
Hadassah Hebrew University Medical Center	RCV000033020	SCV004099504	pathogenic	Primary ciliary dyskinesia 19		criteria provided, single submitter	clinical testing
Institute Of Molecular Biology And Genetics, Federal Almazov National Medical Research Centre	RCV002460894	SCV004176743	pathogenic	Primary ciliary dyskinesia	2023-12-11	criteria provided, single submitter	clinical testing	ACMG: PP5, PP3, PM2, BP1. The variant has multiple records in ClinVar with pathogenic interpretation (Variation ID: 39798)
Clinical Genetics Laboratory, Skane University Hospital Lund	RCV004696644	SCV005197745	pathogenic	not provided	2022-07-13	criteria provided, single submitter	clinical testing
GeneDx	RCV004696644	SCV005870252	likely pathogenic	not provided	2024-08-22	criteria provided, single submitter	clinical testing	In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 34426522, 31589614, 38193396, 34693619, 23527195, 34215651, 33726816, 31879361, 23891469, 35768906, 31980526, 33635866, 33447612, 37077557, 23122589)
OMIM	RCV000033020	SCV000056800	pathogenic	Primary ciliary dyskinesia 19	2012-11-02	no assertion criteria provided	literature only
GeneReviews	RCV000033020	SCV000086955	not provided	Primary ciliary dyskinesia 19		no assertion provided	literature only
Pediatric Genetics Clinic, Sheba Medical Center	RCV001731475	SCV001572803	pathogenic	Heterotaxy	2021-04-24	no assertion criteria provided	research