NM_012144.4(DNAI1):c.1222G>A (p.Val408Met) AND Primary ciliary dyskinesia

Germline classification:: Pathogenic (1 submission)
Last evaluated:: Jan 9, 2024
Review status:: 1 star out of maximum of 4 stars
criteria provided, single submitter

Somatic classification of clinical impact:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Somatic classification of oncogenicity:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Record status:: current
Accession:: RCV000696257.10

Allele description [Variation Report for NM_012144.4(DNAI1):c.1222G>A (p.Val408Met)]

NM_012144.4(DNAI1):c.1222G>A (p.Val408Met)

Gene:

DNAI1:dynein axonemal intermediate chain 1 [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

9p13.3

Genomic location:

Preferred name:

NM_012144.4(DNAI1):c.1222G>A (p.Val408Met)

HGVS:

NC_000009.12:g.34506785G>A
NG_008127.1:g.52973G>A
NM_001281428.2:c.1234G>A
NM_012144.4:c.1222G>AMANE SELECT
NP_001268357.1:p.Val412Met
NP_036276.1:p.Val408Met
NC_000009.11:g.34506783G>A
NM_012144.3:c.1222G>A

Protein change:

V408M

Links:

dbSNP: rs794727103

NCBI 1000 Genomes Browser:

rs794727103

Molecular consequence:

NM_001281428.2:c.1234G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_012144.4:c.1222G>A - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Name:: Primary ciliary dyskinesia
Synonyms:: Ciliary dyskinesia
Identifiers:: MONDO: MONDO:0016575; MedGen: C0008780; OMIM: PS244400; Human Phenotype Ontology: HP:0012265

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000824809	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Jan 9, 2024)	germline	clinical testing	PubMed (2) [See all records that cite these PMIDs] 16858015, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000824809

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Pathogenic
(Jan 9, 2024)

germline

clinical testing

PubMed (2)
[See all records that cite these PMIDs]

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

Mutations of DNAI1 in primary ciliary dyskinesia: evidence of founder effect in a common mutation.

Zariwala MA, Leigh MW, Ceppa F, Kennedy MP, Noone PG, Carson JL, Hazucha MJ, Lori A, Horvath J, Olbrich H, Loges NT, Bridoux AM, Pennarun G, Duriez B, Escudier E, Mitchison HM, Chodhari R, Chung EM, Morgan LC, de Iongh RU, Rutland J, Pradal U, et al.

Am J Respir Crit Care Med. 2006 Oct 15;174(8):858-66. Epub 2006 Jul 20.

PubMed [citation]

PMID:: 16858015
PMCID:: PMC2648054

Sherloc: a comprehensive refinement of the ACMG-AMP variant classification criteria.

Nykamp K, Anderson M, Powers M, Garcia J, Herrera B, Ho YY, Kobayashi Y, Patil N, Thusberg J, Westbrook M; Invitae Clinical Genomics Group., Topper S.

Genet Med. 2017 Oct;19(10):1105-1117. doi: 10.1038/gim.2017.37. Epub 2017 May 11. Erratum in: Genet Med. 2020 Jan;22(1):240. doi: 10.1038/s41436-019-0624-9.

PubMed [citation]

PMID:: 28492532
PMCID:: PMC5632818

Details of each submission

From Labcorp Genetics (formerly Invitae), Labcorp, SCV000824809.7

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (2)

Description

This sequence change replaces valine, which is neutral and non-polar, with methionine, which is neutral and non-polar, at codon 408 of the DNAI1 protein (p.Val408Met). This variant is present in population databases (rs794727103, gnomAD 0.004%). This missense change has been observed in individual(s) with clinical features of primary ciliary dyskinesia (PMID: 16858015; Invitae). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 194245). 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 DNAI1 protein function with a positive predictive value of 80%. For these reasons, this variant has been classified as Pathogenic.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

Last Updated: Sep 29, 2024

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