NM_080860.4(RSPH1):c.85G>T (p.Glu29Ter) AND Primary ciliary dyskinesia

Germline classification:: Pathogenic (2 submissions)
Last evaluated:: Jan 14, 2024
Review status:: 2 stars out of maximum of 4 stars
criteria provided, multiple submitters, no conflicts

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:: RCV000543760.23

Allele description [Variation Report for NM_080860.4(RSPH1):c.85G>T (p.Glu29Ter)]

NM_080860.4(RSPH1):c.85G>T (p.Glu29Ter)

Genes:

LOC126653391:CDK7 strongly-dependent group 2 enhancer GRCh37_chr21:43912470-43913669 [Gene]
RSPH1:radial spoke head component 1 [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

21q22.3

Genomic location:

Preferred name:

NM_080860.4(RSPH1):c.85G>T (p.Glu29Ter)

Other names:

RSPH1, GLU29TER (rs138320978); p.Glu29*

HGVS:

NC_000021.9:g.42493049C>A
NG_034257.1:g.8306G>T
NM_001286506.2:c.55-186G>T
NM_080860.4:c.85G>TMANE SELECT
NP_543136.1:p.Glu29Ter
NP_543136.1:p.Glu29Ter
NP_543136.1:p.Glu29Ter
NC_000021.8:g.43913159C>A
NM_080860.2:c.85G>T
NM_080860.3:c.85G>T
p.Glu29X

Protein change:

E29*; GLU29TER

Links:

OMIM: 609314.0001; dbSNP: rs138320978

NCBI 1000 Genomes Browser:

rs138320978

Molecular consequence:

NM_001286506.2:c.55-186G>T - intron variant - [Sequence Ontology: SO:0001627]
NM_080860.4:c.85G>T - nonsense - [Sequence Ontology: SO:0001587]

Observations:

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
SCV000624464	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Jan 14, 2024)	germline	clinical testing	PubMed (5) [See all records that cite these PMIDs] 23993197, 24518672, 24568568, 26139845, 28492532
SCV000711668	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	criteria provided, single submitter (LMM Criteria)	Pathogenic (Jul 27, 2017)	germline	clinical testing	PubMed (5) [See all records that cite these PMIDs] 26139845, 24568568, 23993197, 24518672, 24033266

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000624464

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Pathogenic
(Jan 14, 2024)

germline

clinical testing

PubMed (5)
[See all records that cite these PMIDs]

SCV000711668

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

criteria provided, single submitter

(LMM Criteria)

Pathogenic
(Jul 27, 2017)

germline

clinical testing

PubMed (5)
[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
not provided	germline	not provided	2	2	not provided	not provided	not provided	clinical testing

Citations

PubMed

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

Whole-Exome Sequencing and Targeted Copy Number Analysis in Primary Ciliary Dyskinesia.

Marshall CR, Scherer SW, Zariwala MA, Lau L, Paton TA, Stockley T, Jobling RK, Ray PN, Knowles MR; FORGE Canada Consortium, Hall DA, Dell SD, Kim RH.

G3 (Bethesda). 2015 Jul 2;5(8):1775-81. doi: 10.1534/g3.115.019851.

PubMed [citation]

PMID:: 26139845
PMCID:: PMC4528333

See all PubMed Citations (6)

Details of each submission

From Labcorp Genetics (formerly Invitae), Labcorp, SCV000624464.9

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (5)

Description

This sequence change creates a premature translational stop signal (p.Glu29*) in the RSPH1 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in RSPH1 are known to be pathogenic (PMID: 23993197). This variant is present in population databases (rs138320978, gnomAD 0.06%). This premature translational stop signal has been observed in individuals with primary ciliary dyskinesia (PMID: 23993197, 24518672, 24568568, 26139845). ClinVar contains an entry for this variant (Variation ID: 66987). 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.

#	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

From Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine, SCV000711668.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	2	not provided	not provided	clinical testing	PubMed (5)

Description

The p.Glu29X (NM_080860.2 c.85G>T) variant in RSPH1 has been previously reported in at least 5 homozygous and 5 compound heterozygous individuals with primary ciliary dyskinesia (Kott 2013, Marshall 2015, Onoufriadis 2014, Knowles 2014). T his variant has been identified in 40/126,700 of European chromosomes by the Gen ome Aggregation Database (gnomAD, http://gnomAD.broadinstitute.org; dbSNP rs1383 20978). Although this variant has been seen in the general population, its frequ ency is low enough to be consistent with a recessive carrier frequency. This non sense variant leads to a premature termination codon at position 29, which is pr edicted to lead to a truncated or absent protein. Biallelic loss of function of the RSPH1 gene has been associated with primary ciliary dyskinesia. In summary, this variant meets criteria to be classified as pathogenic for primary ciliary d yskinesia in an autosomal recessive manner based upon its biallelic occurrence i n individuals with this disease and the predicted impact on the protein. ACMG/AM P criteria applied: PVS1, PM3 (upgraded to Strong based on multiple occurrences) .

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	not provided	not provided	not provided	not provided		2	not provided	2	not provided

Last Updated: Nov 24, 2024

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