X-640851-C-T

Variant names:

• chrX-640851-C-T
• rs137852556
• NM_000451.4:c.517C>T

Variant summary

Our verdict is Pathogenic. The variant received 19 ACMG points: 19P and 0B. PM1 PM2 PM5 PP2 PP3_Strong PP5_Very_Strong

The NM_000451.4(SHOX):​c.517C>T​(p.Arg173Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000205 in 1,461,668 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 1 hemizygotes in GnomAD. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R173H) has been classified as Pathogenic.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000021 (0 hom. 1 hem.)
• Consequence: SHOX NM_000451.4 missense
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:7
• Conservation: PhyloP100: 0.191
• Publications: 0 publications found

Genes affected

SHOX (HGNC:10853): (SHOX homeobox) This gene belongs to the paired homeobox family and is located in the pseudoautosomal region 1 (PAR1) of X and Y chromosomes. Defects in this gene are associated with idiopathic growth retardation and in the short stature phenotype of Turner syndrome patients. This gene is highly conserved across species from mammals to fish to flies. Alternatively spliced transcript variants encoding different isoforms have been noted for this gene. [provided by RefSeq, Jul 2008]

SHOX Gene-Disease associations (from GenCC):

• Leri-Weill dyschondrosteosis

  Inheritance: XL, AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: G2P, Orphanet, Labcorp Genetics (formerly Invitae), Ambry Genetics
• Langer mesomelic dysplasia

  Inheritance: Unknown, XL, AR Classification: DEFINITIVE, STRONG, MODERATE, SUPPORTIVE Submitted by: Ambry Genetics, G2P, Orphanet, Labcorp Genetics (formerly Invitae)
• SHOX-related short stature

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Pathogenic. The variant received 19 ACMG points.

• PM1: In a hotspot region, there are 7 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 3 uncertain in NM_000451.4
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chrX-640852-G-A is described in ClinVar as Pathogenic. ClinVar VariationId is 1256555.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• PP2: Missense variant in the gene, where a lot of missense mutations are associated with disease in ClinVar. The gene has 17 curated pathogenic missense variants (we use a threshold of 10). The gene has 1 curated benign missense variants. Gene score misZ: -0.53811 (below the threshold of 3.09). Trascript score misZ: NaN (below the threshold of 3.09). GenCC associations: The gene is linked to Leri-Weill dyschondrosteosis, Langer mesomelic dysplasia, SHOX-related short stature.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.975
• PP5: Variant X-640851-C-T is Pathogenic according to our data. Variant chrX-640851-C-T is described in ClinVar as Pathogenic. ClinVar VariationId is 9878.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SHOX	NM_000451.4	c.517C>T	p.Arg173Cys	missense_variant	Exon 3 of 5	ENST00000686671.1	NP_000442.1
SHOX	NM_006883.2	c.517C>T	p.Arg173Cys	missense_variant	Exon 4 of 6		NP_006874.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SHOX	ENST00000686671.1	c.517C>T	p.Arg173Cys	missense_variant	Exon 3 of 5		NM_000451.4	ENSP00000508521.1
SHOX	ENST00000381575.6	c.517C>T	p.Arg173Cys	missense_variant	Exon 3 of 5	1		ENSP00000370987.1
SHOX	ENST00000381578.6	c.517C>T	p.Arg173Cys	missense_variant	Exon 4 of 6	5		ENSP00000370990.1
SHOX	ENST00000334060.8	c.517C>T	p.Arg173Cys	missense_variant	Exon 4 of 6	5		ENSP00000335505.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000205 AC: 3 AN: 1461668 Hom.: 0 Cov.: 33 AF XY: 0.00000138 AC XY: 1 AN XY: 727146

African (AFR) AF: 0.00 AC: 0 AN: 33472

American (AMR) AF: 0.00 AC: 0 AN: 44716

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26132

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.00 AC: 0 AN: 86250

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53420

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5762

European-Non Finnish (NFE) AF: 0.00000270 AC: 3 AN: 1111838

Other (OTH) AF: 0.00 AC: 0 AN: 60378

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Leri-Weill dyschondrosteosis Pathogenic:3

Jun 15, 2002

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

May 01, 2016

Baylor Genetics

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

Our laboratory reported dual molecular diagnoses in ALG6 (NM_013339.3:c.257+5G>A; NM_013339.3:c.988G>T; in trans) and SHOX (NM_000451.3:c.517C>T) in an individual with mild hypotonia, poor feeding, congenital heart disease (VSD, PFO, PDA), seizure disorder, dysmorphic facies, small chest wall, bowed lower legs, apparently short upper extremities, shallow sacral dimple, small for gestational age and a history of prematurity and intrauterine growth restriction. -

Jan 07, 2023

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: SHOX c.517C>T (p.Arg173Cys) results in a non-conservative amino acid change located in the Homeobox domain (IPR001356) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 251182 control chromosomes. c.517C>T has been reported in the literature in a consanguineous family demonstrating a pseudodominant inheritance pattern with multiple individuals affected with Langer Mesomelic Dysplasia (homozygous genotype) or Leri-Weill Dyschondrosteosis (hemizygous or heterozygous genotype) and as a de-novo variant in settings of exome sequencing performed in infants with a dual molecular diagnosis of Leri-Weill Dyschondrosteosis and autosomal recessive Congenital disorder of glycosylation, type Ic (example, Meng_2017). These data indicate that the variant is very likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function reporting impaired nuclear localization, impaired DNA binding ability and roughly 50% decrease in homodimerization ability (Schneider_2005). Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -

not provided Pathogenic:3

Aug 22, 2023

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Published functional studies demonstrate a damaging effect (reduced dimerization ability) (PMID: 15931687); Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 19309509, 27959697, 24421874, 20148114, 11403039, 21262861, 12116253, 15173321, 28973083, 36307859, 15931687) -

Sep 10, 2024

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The SHOX c.517C>T; p.Arg173Cys variant (rs137852556, ClinVar Variation ID: 9878) is reported in the literature in a consanguineous family in heterozygous individuals with Leri-Weill dyschondrosteosis and homozygous individuals with Langer mesomelic dysplasia (Shears 2002) and was found to segregate with disease in a second family with dyschondrosteosis (Huber 2001). In addition, this variant is reported in exome studies in individuals who have a SHOX-related phenotype (Fu 2022, Meng 2017). This variant is absent from the Genome Aggregation Database (v2.1.1), indicating it is not a common polymorphism. Functional analyses of the variant protein show this variant impairs nuclear localization and DNA binding ability (Sabherwal 2004, Schneider 2005). Computational analyses are uncertain whether this variant is neutral or deleterious (REVEL: 0.692). Based on available information, this variant is considered to be pathogenic. References: Fu F et al. Application of exome sequencing for prenatal diagnosis of fetal structural anomalies: clinical experience and lessons learned from a cohort of 1618 fetuses. Genome Med. 2022 Oct 28;14(1):123. PMID: 36307859. Huber C et al. SHOX point mutations in dyschondrosteosis. J Med Genet. 2001 May;38(5):323. PMID: 11403039. Meng L et al. Use of Exome Sequencing for Infants in Intensive Care Units: Ascertainment of Severe Single-Gene Disorders and Effect on Medical Management. JAMA Pediatr. 2017 Dec 4;171(12):e173438. PMID: 28973083. Sabherwal N et al. Impairment of SHOX nuclear localization as a cause for Léri-Weill syndrome. J Cell Sci. 2004 Jun 15;117(Pt 14):3041-8. PMID: 15173321. Schneider KU et al. Alteration of DNA binding, dimerization, and nuclear translocation of SHOX homeodomain mutations identified in idiopathic short stature and Leri-Weill dyschondrosteosis. Hum Mutat. 2005 Jul;26(1):44-52. PMID: 15931687. Shears DJ et al. Pseudodominant inheritance of Langer mesomelic dysplasia caused by a SHOX homeobox missense mutation. Am J Med Genet. 2002 Jun 15;110(2):153-7. PMID: 12116253. -

Jul 29, 2015

Eurofins Ntd Llc (ga)

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

SHOX-related disorder Pathogenic:1

Jun 04, 2024

PreventionGenetics, part of Exact Sciences

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

The SHOX c.517C>T variant is predicted to result in the amino acid substitution p.Arg173Cys. This variant in the heterozygous condition was reported to be pathogenic for Leri-Weill Dyschondrosteosis (see Family 8, Huber et al. 2001. PubMed ID: 11403039). In the compound heterozygous condition, this variant was reported to be pathogenic for Langer mesomelic dysplasia (Kant et al. 2011. PubMed ID: 21068148). This variant was also reported as a de novo variant in one patient with dual diagnosis who also had two compound heterozygous ALG6 variants (see eTable 4, Meng et al. 2017. PubMed ID: 28973083). Functional studies suggest that the p.Arg173Cys variant led to disrupted protein nuclear localization (Sabherwal et al. 2004. PubMed ID: 15173321). In summary, we consider this variant pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.63	D
BayesDel_noAF	Pathogenic	0.66
CADD	Benign	19
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.85	D;.;.
FATHMM_MKL	Benign	0.54	D
LIST_S2	Pathogenic	0.99	D;D;.
M_CAP	Pathogenic	0.75	D
MetaRNN	Pathogenic	0.97	D;D;D
MetaSVM	Pathogenic	0.80	D
MutationAssessor	Pathogenic	4.8	H;H;H
PhyloP100		0.19
PrimateAI	Pathogenic	0.95	D
PROVEAN	Pathogenic	-7.2	D;D;D
REVEL	Pathogenic	0.69
Sift	Pathogenic	0.0	D;D;D
Sift4G	Pathogenic	0.0	D;D;D
Polyphen		1.0	D;D;D
Vest4		0.89
MutPred		0.84		Loss of MoRF binding (P = 0.0141);Loss of MoRF binding (P = 0.0141);Loss of MoRF binding (P = 0.0141);
MVP		1.0
MPC		1.8
ClinPred		0.98	D
GERP RS		0.30
Varity_R		0.90

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs137852556; hg19: chrX-601586; COSMIC: COSV61862044;