Submissions for variant NM_012472.6(DNAAF11):c.2T>A (p.Met1Lys)

gnomAD frequency: 0.00004  dbSNP: rs377278570

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000650320	SCV000772161	pathogenic	Primary ciliary dyskinesia 19	2023-09-11	criteria provided, single submitter	clinical testing	This sequence change affects the initiator methionine of the LRRC6 mRNA. The next in-frame methionine is located at codon 121. This variant is present in population databases (rs377278570, gnomAD 0.03%). This variant has not been reported in the literature in individuals affected with LRRC6-related conditions. ClinVar contains an entry for this variant (Variation ID: 540324). This variant disrupts a region of the LRRC6 protein in which other variant(s) (p.Ile100Thr) have been determined to be pathogenic (PMID: 27637300). This suggests that this is a clinically significant region of the protein, and that variants that disrupt it are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic.
Ambry Genetics	RCV002461967	SCV002755443	likely pathogenic	Primary ciliary dyskinesia	2023-09-08	criteria provided, single submitter	clinical testing	The p.M1? pathogenic mutation (also known as c.2T>A) is located in coding exon 1 of the LRRC6 gene and results from a T to A substitution at nucleotide position 2. This alters the methionine residue at the initiation codon. Sequence variations that modify the initiation codon are expected to result in either loss of translation initiation, N-terminal truncation, or cause a shift in the mRNA reading frame. However, there is an alternative initiation (or start) codon in other clinically/biologically relevant transcript(s). Based on the majority of available evidence to date, this variant is likely to be pathogenic.
PreventionGenetics, part of Exact Sciences	RCV003403499	SCV004104724	uncertain significance	DNAAF11-related disorder	2023-07-01	criteria provided, single submitter	clinical testing	The DNAAF11 c.2T>A variant is predicted to disrupt the translation initiation site (Start loss). To our knowledge, this variant has not been reported in the literature. This variant is reported in 0.027% of alleles in individuals of African descent in gnomAD (http://gnomad.broadinstitute.org/variant/8-133687738-A-T). Although we suspect that this variant may be pathogenic, at this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV003736869	SCV004563741	likely pathogenic	not provided	2023-08-30	criteria provided, single submitter	clinical testing	The DNAAF11 c.2T>A; p.Met1? variant (rs377278570), to our knowledge, is not reported in the medical literature but is reported in ClinVar (Variation ID: 540324). This variant is found in the African/African-American population with an allele frequency of 0.027% (6/22,344 alleles) in the Genome Aggregation Database. Additionally, a downstream truncating variant has been described in an individual with primary ciliary dyskinesia and is considered pathogenic (Tinoco 2023). The p.Met1 variant abolishes the canonical translation initiation site, which is likely to disrupt gene function. Based on available information, this variant is considered to be likely pathogenic. References: Tinoco EM et al. Primary Ciliary Dyskinesia in a Portuguese Bronchiectasis Outpatient Clinic. Genes (Basel). 2023 Feb 21;14(3):541. PMID: 36980814.