VCV002428621.4 - ClinVar

NM_000451.4(SHOX):c.582C>A (p.Cys194Ter)

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.

(2)

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.

Pathogenic

criteria provided, multiple submitters, no conflicts

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

Identifiers

NM_000451.4(SHOX):c.582C>A (p.Cys194Ter)

Variation ID: 2428621 Accession: VCV002428621.4

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: Xp22.33 Yp11.2 X: 641036 (GRCh38) [ NCBI UCSC ] Y: 641036 (GRCh38) [ NCBI UCSC ] X: 601771 (GRCh37) [ NCBI UCSC ] Y: 551771 (GRCh37) [ 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	Feb 13, 2023	Sep 29, 2024	Aug 25, 2023

HGVS

Nucleotide	Protein	Molecular consequence
NM_000451.4:c.582C>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_000442.1:p.Cys194Ter	nonsense
NM_000451.3:c.582C>A
NM_006883.2:c.582C>A	NP_006874.1:p.Cys194Ter	nonsense
NC_000023.11:g.641036C>A
NC_000024.10:g.641036C>A
NC_000023.10:g.601771C>A
NC_000024.9:g.551771C>A
NG_009385.2:g.21693C>A
LRG_710:g.21693C>A
LRG_710t1:c.582C>A	LRG_710p1:p.Cys194Ter
LRG_710t2:c.582C>A	LRG_710p2:p.Cys194Ter

... more HGVS ... less HGVS

Protein change

C194*

Other names

Canonical SPDI

NC_000024.10:641035:C: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	164	363

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.
not provided	Pathogenic (2)	criteria provided, multiple submitters, no conflicts	Aug 25, 2023	RCV003120222.4

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.
Pathogenic (Apr 13, 2022)	criteria provided, single submitter (ARUP Molecular Germline Variant Investigation Process 2021) Method: clinical testing	not provided Affected status: unknown Allele origin: germline	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories Accession: SCV003800124.2 First in ClinVar: Feb 13, 2023 Last updated: Mar 04, 2023	Comment: The SHOX c.582C>A; p.Cys194Ter variant is reported to segregate with disease in a family with short stature (Sandberg 2017). This variant is absent from general … (more) The SHOX c.582C>A; p.Cys194Ter variant is reported to segregate with disease in a family with short stature (Sandberg 2017). This variant is absent from general population databases (Exome Variant Server, Genome Aggregation Database), indicating it is not a common polymorphism. This variant induces an early termination codon and is predicted to result in a truncated protein or mRNA subject to nonsense-mediated decay. Additionally, other variants that introduce a premature termination codon have been described in this region and are considered pathogenic (Gursoy 2020, Joustra 2019). Based on available information, this variant is classified as pathogenic. References: Gursoy S et al. Detection of SHOX Gene Variations in Patients with Skeletal Abnormalities with or without Short Stature. J Clin Res Pediatr Endocrinol. 2020 Nov 25;12(4):358-365. PMID: 32295321. Joustra SD et al. Novel Clinical Criteria Allow Detection of Short Stature Homeobox-Containing Gene Haploinsufficiency Caused by Either Gene or Enhancer Region Defects. Horm Res Paediatr. 2019;92(6):372-381. PMID: 32344414. Sandberg ES et al. Short Stature Homeobox-Containing Haploinsufficiency in Seven Siblings with Short Stature. Case Rep Endocrinol. 2017;2017:7287351. PMID: 28948052. (less)
Pathogenic (Aug 25, 2023)	criteria provided, single submitter (GeneDx Variant Classification Process June 2021) Method: clinical testing	Not Provided Affected status: yes Allele origin: germline	GeneDx Accession: SCV005325968.1 First in ClinVar: Sep 29, 2024 Last updated: Sep 29, 2024	Comment: Nonsense variant predicted to result in protein truncation, as the last 99 amino acids are lost, and other loss-of-function variants have been reported downstream in … (more) Nonsense variant predicted to result in protein truncation, as the last 99 amino acids are lost, and other loss-of-function variants have been reported downstream in HGMD; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 25525159, 28948052) (less)

Comment:

The SHOX c.582C>A; p.Cys194Ter variant is reported to segregate with disease in a family with short stature (Sandberg 2017). This variant is absent from general population databases (Exome Variant Server, Genome Aggregation Database), indicating it is not a common polymorphism. This variant induces an early termination codon and is predicted to result in a truncated protein or mRNA subject to nonsense-mediated decay. Additionally, other variants that introduce a premature termination codon have been described in this region and are considered pathogenic (Gursoy 2020, Joustra 2019). Based on available information, this variant is classified as pathogenic. References: Gursoy S et al. Detection of SHOX Gene Variations in Patients with Skeletal Abnormalities with or without Short Stature. J Clin Res Pediatr Endocrinol. 2020 Nov 25;12(4):358-365. PMID: 32295321. Joustra SD et al. Novel Clinical Criteria Allow Detection of Short Stature Homeobox-Containing Gene Haploinsufficiency Caused by Either Gene or Enhancer Region Defects. Horm Res Paediatr. 2019;92(6):372-381. PMID: 32344414. Sandberg ES et al. Short Stature Homeobox-Containing Haploinsufficiency in Seven Siblings with Short Stature. Case Rep Endocrinol. 2017;2017:7287351. PMID: 28948052.

Comment:

Nonsense variant predicted to result in protein truncation, as the last 99 amino acids are lost, and other loss-of-function variants have been reported downstream in HGMD; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 25525159, 28948052)

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

There are no citations for germline classification of this variant in ClinVar. If you know of citations for this variation, please consider submitting that information to ClinVar.

Text-mined citations for this variant ...

Record last updated Oct 08, 2024

ClinVar Genomic variation as it relates to human health

NM_000451.4(SHOX):c.582C>A (p.Cys194Ter)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for this variant ...