rs137852556
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PM1PM2PM5PP3_StrongPP5_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
Consequence
NM_000451.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 18 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
SHOX | NM_000451.4 | c.517C>T | p.Arg173Cys | missense_variant | 3/5 | ENST00000686671.1 | |
SHOX | NM_006883.2 | c.517C>T | p.Arg173Cys | missense_variant | 4/6 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
SHOX | ENST00000686671.1 | c.517C>T | p.Arg173Cys | missense_variant | 3/5 | NM_000451.4 | P1 | ||
SHOX | ENST00000381575.6 | c.517C>T | p.Arg173Cys | missense_variant | 3/5 | 1 | |||
SHOX | ENST00000381578.6 | c.517C>T | p.Arg173Cys | missense_variant | 4/6 | 5 | P1 | ||
SHOX | ENST00000334060.8 | c.517C>T | p.Arg173Cys | missense_variant | 4/6 | 5 |
Frequencies
GnomAD3 genomes ? Cov.: 32
GnomAD4 exome AF: 0.00000205 AC: 3AN: 1461668Hom.: 0 Cov.: 33 AF XY: 0.00000138 AC XY: 1AN XY: 727146
GnomAD4 genome ? Cov.: 32
ClinVar
Submissions by phenotype
Leri-Weill dyschondrosteosis Pathogenic:3
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. - |
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. - |
not provided Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Eurofins Ntd Llc (ga) | Jul 29, 2015 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at