NM_000451.4(SHOX):c.675_676insA (p.Pro226fs) AND Leri-Weill dyschondrosteosis

Germline classification:: Likely pathogenic (1 submission)
Last evaluated:: Mar 14, 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:: RCV004006253.1

Allele description [Variation Report for NM_000451.4(SHOX):c.675_676insA (p.Pro226fs)]

NM_000451.4(SHOX):c.675_676insA (p.Pro226fs)

Gene:

SHOX:SHOX homeobox [Gene - OMIM - OMIM - HGNC]

Variant type:

Insertion

Cytogenetic location:

Xp22.33

Genomic location:

Preferred name:

NM_000451.4(SHOX):c.675_676insA (p.Pro226fs)

HGVS:

NC_000023.11:g.644432_644433insA
NC_000024.10:g.644432_644433insA
NG_009385.2:g.25089_25090insA
NM_000451.4:c.675_676insAMANE SELECT
NM_006883.2:c.633+3345_633+3346insA
NP_000442.1:p.Pro226fs
LRG_710t1:c.675_676insA
LRG_710t2:c.633+3345_633+3346insA
LRG_710:g.25089_25090insA
LRG_710p1:p.Pro226fs
NC_000023.10:g.605167_605168insA
NC_000024.9:g.555167_555168insA
NM_000451.3:c.675_676insA

Protein change:

P226fs

Molecular consequence:

NM_000451.4:c.675_676insA - frameshift variant - [Sequence Ontology: SO:0001589]
NM_006883.2:c.633+3345_633+3346insA - intron variant - [Sequence Ontology: SO:0001627]

Condition(s)

Name:: Leri-Weill dyschondrosteosis (LWD)
Synonyms:: Dyschondrosteosis; Léri-Weill dyschondrosteosis
Identifiers:: MONDO: MONDO:0007481; MedGen: C0265309; OMIM: 127300

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV004814173	MVZ Dr. Eberhard & Partner Dortmund	criteria provided, single submitter (ACMG Guidelines, 2015)	Likely pathogenic (Mar 14, 2024)	unknown	clinical testing	PubMed (2) [See all records that cite these PMIDs] 30192042, 25741868

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV004814173

MVZ Dr. Eberhard & Partner Dortmund

criteria provided, single submitter

(ACMG Guidelines, 2015)

Likely pathogenic
(Mar 14, 2024)

unknown

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	unknown	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

Recommendations for interpreting the loss of function PVS1 ACMG/AMP variant criterion.

Abou Tayoun AN, Pesaran T, DiStefano MT, Oza A, Rehm HL, Biesecker LG, Harrison SM; ClinGen Sequence Variant Interpretation Working Group (ClinGen SVI).

Hum Mutat. 2018 Nov;39(11):1517-1524. doi: 10.1002/humu.23626. Epub 2018 Sep 7.

PubMed [citation]

PMID:: 30192042
PMCID:: PMC6185798

Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology.

Richards S, Aziz N, Bale S, Bick D, Das S, Gastier-Foster J, Grody WW, Hegde M, Lyon E, Spector E, Voelkerding K, Rehm HL; ACMG Laboratory Quality Assurance Committee.

Genet Med. 2015 May;17(5):405-24. doi: 10.1038/gim.2015.30. Epub 2015 Mar 5.

PubMed [citation]

PMID:: 25741868
PMCID:: PMC4544753

Details of each submission

From MVZ Dr. Eberhard & Partner Dortmund, SCV004814173.1

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

Description

c.675_676insA for p.(Pro226Thrfs*165) in SHOX has not been described in the literature so far, nor is it found in reference populations of different ethnicities. The variant is expected to result in an elongation of the protein (not predicted to undergo "non-stop-decay"). The highly conserved OAR domain, which is required for protein function is located within the region affected by the frameshift. A loss of function of the SHOX protein (transcript variant SHOXa) is to be expected. Other variants that are expected to lead to a loss of the OAR domain (loss of function due to frameshift variants or premature stop codon) are listed as pathogenic in databases and literature. Classification under (additional) consideration of Durkie et al., 2014 and Tayoun et al., 2018 (PMID: 30192042).

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

Last Updated: Apr 20, 2024

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