NM_001377.3(DYNC2H1):c.1953G>A (p.Lys651=) AND Jeune thoracic dystrophy

Germline classification:: Pathogenic (3 submissions)
Last evaluated:: Sep 6, 2023
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:: RCV000515832.4

Allele description [Variation Report for NM_001377.3(DYNC2H1):c.1953G>A (p.Lys651=)]

NM_001377.3(DYNC2H1):c.1953G>A (p.Lys651=)

Gene:

DYNC2H1:dynein cytoplasmic 2 heavy chain 1 [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

11q22.3

Genomic location:

Preferred name:

NM_001377.3(DYNC2H1):c.1953G>A (p.Lys651=)

HGVS:

NC_000011.10:g.103129005G>A
NG_016423.2:g.24575G>A
NM_001080463.2:c.1953G>A
NM_001377.3:c.1953G>AMANE SELECT
NP_001073932.1:p.Lys651=
NP_001368.2:p.Lys651=
NC_000011.9:g.102999734G>A
NG_016423.1:g.24575G>A
NM_001080463.1:c.1953G>A
NM_001377.2:c.1953G>A
p.Lys651Lys

Links:

dbSNP: rs1178331074

NCBI 1000 Genomes Browser:

rs1178331074

Molecular consequence:

NM_001080463.2:c.1953G>A - synonymous variant - [Sequence Ontology: SO:0001819]
NM_001377.3:c.1953G>A - synonymous variant - [Sequence Ontology: SO:0001819]

Condition(s)

Name:: Jeune thoracic dystrophy (ATD1)
Synonyms:: Jeune syndrome; Infantile thoracic dystrophy; Thoracic pelvic phalangeal dystrophy; See all synonyms [MedGen]
Identifiers:: MONDO: MONDO:0018770; MedGen: C0265275; OMIM: PS208500

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000611942	Dan Cohn Lab, University Of California Los Angeles	no assertion criteria provided	Pathogenic (Jun 1, 2017)	maternal	research	PubMed (1) [See all records that cite this PMID]
SCV001479371	University of Washington Center for Mendelian Genomics, University of Washington	no assertion criteria provided	Likely pathogenic	inherited	research	PubMed (1) [See all records that cite this PMID]
SCV004301920	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Sep 6, 2023)	germline	clinical testing	PubMed (6) [See all records that cite these PMIDs] 23456818, 27353043, 29068549, 17576681, 9536098, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000611942

Dan Cohn Lab, University Of California Los Angeles

no assertion criteria provided

Pathogenic
(Jun 1, 2017)

maternal

research

PubMed (1)
[See all records that cite this PMID]

SCV001479371

University of Washington Center for Mendelian Genomics, University of Washington

no assertion criteria provided

Likely pathogenic

inherited

research

PubMed (1)
[See all records that cite this PMID]

SCV004301920

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Pathogenic
(Sep 6, 2023)

germline

clinical testing

PubMed (6)
[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	inherited	yes	not provided	not provided	not provided	not provided	not provided	research
not provided	maternal	yes	not provided	not provided	not provided	not provided	not provided	research

Citations

PubMed

Exome sequencing identifies DYNC2H1 mutations as a common cause of asphyxiating thoracic dystrophy (Jeune syndrome) without major polydactyly, renal or retinal involvement.

Schmidts M, Arts HH, Bongers EM, Yap Z, Oud MM, Antony D, Duijkers L, Emes RD, Stalker J, Yntema JB, Plagnol V, Hoischen A, Gilissen C, Forsythe E, Lausch E, Veltman JA, Roeleveld N, Superti-Furga A, Kutkowska-Kazmierczak A, Kamsteeg EJ, Elçioğlu N, van Maarle MC, et al.

J Med Genet. 2013 May;50(5):309-23. doi: 10.1136/jmedgenet-2012-101284. Epub 2013 Mar 1.

PubMed [citation]

PMID:: 23456818
PMCID:: PMC3627132

Experience of a multidisciplinary task force with exome sequencing for Mendelian disorders.

Fokstuen S, Makrythanasis P, Hammar E, Guipponi M, Ranza E, Varvagiannis K, Santoni FA, Albarca-Aguilera M, Poleggi ME, Couchepin F, Brockmann C, Mauron A, Hurst SA, Moret C, Gehrig C, Vannier A, Bevillard J, Araud T, Gimelli S, Stathaki E, Paoloni-Giacobino A, Bottani A, et al.

Hum Genomics. 2016 Jun 28;10(1):24. doi: 10.1186/s40246-016-0080-4. Review.

PubMed [citation]

PMID:: 27353043
PMCID:: PMC4924303

See all PubMed Citations (6)

Details of each submission

From Dan Cohn Lab, University Of California Los Angeles, SCV000611942.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	research	PubMed (1)

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

From University of Washington Center for Mendelian Genomics, University of Washington, SCV001479371.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	research	PubMed (1)

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

From Labcorp Genetics (formerly Invitae), Labcorp, SCV004301920.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (6)

Description

This sequence change affects codon 651 of the DYNC2H1 mRNA. It is a 'silent' change, meaning that it does not change the encoded amino acid sequence of the DYNC2H1 protein. This variant also falls at the last nucleotide of exon 13, which is part of the consensus splice site for this exon. This variant is present in population databases (no rsID available, gnomAD 0.0009%). This variant has been observed in individual(s) with short-rib polydactyly syndrome or asphyxiating thoracic dystrophy (PMID: 23456818, 27353043, 29068549). 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: 437419). Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). 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

Last Updated: Sep 29, 2024

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