chrX-640851-C-T

Position:

• chrX-640851-C-T

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PM2 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 (★★).

• 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:6
• Conservation: PhyloP100: 0.191

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]

ACMG classification

Verdict is Pathogenic. Variant got 14 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• 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 id is 9878.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-640851-C-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

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

Ensembl

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

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000270

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Leri-Weill dyschondrosteosis Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Jan 07, 2023	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. -
Pathogenic, no assertion criteria provided	literature only	OMIM	Jun 15, 2002	- -
Pathogenic, no assertion criteria provided	clinical testing	Baylor Genetics	May 01, 2016	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. -

not provided Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Aug 22, 2023	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) -
Pathogenic, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jul 29, 2015	- -

SHOX-related disorder Pathogenic:1

Pathogenic, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Jun 04, 2024

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
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
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

Publications

LitVar

Other links and lift over

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