VCV003069196.1 - ClinVar

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

Germline

Classification

The aggregate germline classification for this variant, typically for a monogenic or Mendelian disorder as in the ACMG/AMP guidelines, or for response to a drug. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the aggregate classification.

(1)

Stars represent the aggregate review status, or the level of review supporting the aggregate germline classification for this VCV record. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. The number of submissions which contribute to this review status is shown in parentheses.

Likely pathogenic

criteria provided, single submitter

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

Identifiers

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

Variation ID: 3069196 Accession: VCV003069196.1

Type and length

Insertion, 1 bp

Location

Cytogenetic: Yp11.2 Xp22.33 Y: 644432-644433 (GRCh38) [ NCBI UCSC ] X: 605167-605168 (GRCh37) [ NCBI UCSC ] Y: 555167-555168 (GRCh37) [ NCBI UCSC ] X: 644432-644433 (GRCh38) [ NCBI UCSC ]

Timeline in ClinVar

	First in ClinVar Help The date this variant first appeared in ClinVar with each type of classification.	Last submission Help The date of the most recent submission for each type of classification for this variant.	Last evaluated Help The most recent date that a submitter evaluated this variant for each type of classification.
Germline	Apr 20, 2024	Apr 20, 2024	Mar 14, 2024

HGVS

Nucleotide	Protein	Molecular consequence
NM_000451.4:c.675_676insA MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_000442.1:p.Pro226fs	frameshift
NM_006883.2:c.633+3345_633+3346insA		intron variant
NC_000023.11:g.644432_644433insA
NC_000024.10:g.644432_644433insA
NC_000023.10:g.605167_605168insA
NC_000024.9:g.555167_555168insA
NG_009385.2:g.25089_25090insA
LRG_710:g.25089_25090insA
LRG_710t1:c.675_676insA	LRG_710p1:p.Pro226fs
LRG_710t2:c.633+3345_633+3346insA

... more HGVS ... less HGVS

Protein change

P226fs

Other names

Canonical SPDI

NC_000024.10:644432::A

Functional consequence Help The effect of the variant on RNA or protein function, based on experimental evidence from submitters.

Global minor allele frequency (GMAF) Help The global minor allele frequency calculated by the 1000 Genomes Project. The minor allele at this location is indicated in parentheses and may be different from the allele represented by this VCV record.

Allele frequency Help The frequency of the allele represented by this VCV record.

Links

VarSome

Genes

Gene	OMIM	ClinGen Gene Dosage Sensitivity Curation		Variation Viewer Help Links to Variation Viewer, a genome browser to view variation data from NCBI databases.	Related variants
Gene	OMIM	HI score Help The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team.	TS score Help The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team.		Within gene Help The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants.	All Help The number of variants in ClinVar for this gene, including smaller variants within the gene and larger CNVs that overlap or fully contain the gene.
SHOX		Sufficient evidence for dosage pathogenicity	No evidence available	GRCh38 GRCh38	163	362

Conditions - Germline

Condition Help The condition for this variant-condition (RCV) record in ClinVar.	Classification Help The aggregate germline classification for this variant-condition (RCV) record in ClinVar. The number of submissions that contribute to this aggregate classification is shown in parentheses. (# of submissions)	Review status Help The aggregate review status for this variant-condition (RCV) record in ClinVar. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status.	Last evaluated Help The most recent date that a submitter evaluated this variant for the condition.	Variation/condition record Help The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page.
Leri-Weill dyschondrosteosis	Likely pathogenic (1)	criteria provided, single submitter	Mar 14, 2024	RCV004006253.1

Submissions - Germline

Classification Help The submitted germline classification for each SCV record. (Last evaluated)	Review status Help Stars represent the review status, or the level of review supporting the submitted (SCV) record. This value is calculated by NCBI based on data from the submitter. Read our rules for calculating the review status. This column also includes a link to the submitter’s assertion criteria if provided, and the collection method. (Assertion criteria)	Condition Help The condition for the classification, provided by the submitter for this submitted (SCV) record. This column also includes the affected status and allele origin of individuals observed with this variant.	Submitter Help The submitting organization for this submitted (SCV) record. This column also includes the SCV accession and version number, the date this SCV first appeared in ClinVar, and the date that this SCV was last updated in ClinVar.	More information Help This column includes more information supporting the classification, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter.
Likely pathogenic (Mar 14, 2024)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Leri-Weill dyschondrosteosis Affected status: unknown Allele origin: unknown	MVZ Dr. Eberhard & Partner Dortmund Accession: SCV004814173.1 First in ClinVar: Apr 20, 2024 Last updated: Apr 20, 2024	Publications: PubMed (1) PubMed: 30192042 Comment: c.675_676insA for p.(Pro226Thrfs165) in SHOX has not been described in the literature so far, nor is it found in reference populations of different ethnicities. The … (more) c.675_676insA for p.(Pro226Thrfs165) 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). (less)

Comment:

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).

Germline Functional Evidence

There is no functional evidence in ClinVar for this variation. If you have generated functional data for this variation, please consider submitting that data to ClinVar.

Comment:

Citations for germline classification of this variant

Title	Author	Journal	Year	Link
Recommendations for interpreting the loss of function PVS1 ACMG/AMP variant criterion.	Abou Tayoun AN	Human mutation	2018	PMID: 30192042

Text-mined citations for this variant ...

Record last updated Apr 20, 2024

ClinVar Genomic variation as it relates to human health

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

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for this variant ...