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NM_004273.5(CHST3):c.512_513del (p.Thr171fs) AND Spondyloepiphyseal dysplasia with congenital joint dislocations

Germline classification:
Conflicting interpretations of pathogenicity (2 submissions)
Last evaluated:
Jan 10, 2024
Review status:
criteria provided, conflicting classifications
Somatic classification
of clinical impact:
None
Review status:
(0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided
Somatic classification
of oncogenicity:
None
Review status:
(0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided
Record status:
current
Accession:
RCV000779033.8

Allele description [Variation Report for NM_004273.5(CHST3):c.512_513del (p.Thr171fs)]

NM_004273.5(CHST3):c.512_513del (p.Thr171fs)

Gene:
CHST3:carbohydrate sulfotransferase 3 [Gene - OMIM - HGNC]
Variant type:
Microsatellite
Cytogenetic location:
10q22.1
Genomic location:
Preferred name:
NM_004273.5(CHST3):c.512_513del (p.Thr171fs)
HGVS:
  • NC_000010.11:g.72007541CA[1]
  • NG_012635.1:g.48180CA[1]
  • NM_004273.5:c.512_513delMANE SELECT
  • NP_004264.2:p.Thr171fs
  • NC_000010.10:g.73767299CA[1]
  • NC_000010.10:g.73767299_73767300del
Protein change:
T171fs
Links:
dbSNP: rs1564532120
NCBI 1000 Genomes Browser:
rs1564532120
Molecular consequence:
  • NM_004273.5:c.512_513del - frameshift variant - [Sequence Ontology: SO:0001589]

Condition(s)

Name:
Spondyloepiphyseal dysplasia with congenital joint dislocations (SEDCJD)
Synonyms:
Kozlowski Celermajer Tink syndrome; Humero-spinal dysostosis with congenital heart disease
Identifiers:
MONDO: MONDO:0007738; MedGen: C1837657; Orphanet: 263463; OMIM: 143095

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Assertion and evidence details

Help
Submission AccessionSubmitterReview Status
(Assertion method)		Clinical Significance
(Last evaluated)		OriginMethodCitations
SCV000915481Illumina Laboratory Services, Illumina
criteria provided, single submitter

(ICSL Variant Classification Criteria 09 May 2019)		Uncertain significance
(Oct 10, 2018) 		germlineclinical testing

Citation Link,

SCV003014846Labcorp Genetics (formerly Invitae), Labcorp
criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))		Pathogenic
(Jan 10, 2024) 		germlineclinical testing

PubMed (1)
[See all records that cite this PMID]

Help

Summary from all submissions

EthnicityOriginAffectedIndividualsFamiliesChromosomes testedNumber TestedFamily historyMethod
not providedgermlineunknownnot providednot providednot providednot providednot providedclinical testing

Citations

PubMed

Sherloc: a comprehensive refinement of the ACMG-AMP variant classification criteria.

Nykamp K, Anderson M, Powers M, Garcia J, Herrera B, Ho YY, Kobayashi Y, Patil N, Thusberg J, Westbrook M; Invitae Clinical Genomics Group., Topper S.

Genet Med. 2017 Oct;19(10):1105-1117. doi: 10.1038/gim.2017.37. Epub 2017 May 11. Erratum in: Genet Med. 2020 Jan;22(1):240. doi: 10.1038/s41436-019-0624-9.

PubMed [citation]
PMID:
28492532
PMCID:
PMC5632818

Details of each submission

From Illumina Laboratory Services, Illumina, SCV000915481.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testingnot provided

Description

This variant results in a frameshift and is predicted to result in premature termination of the protein. It was observed by ICSL as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018) and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score for this variant, it could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene and cDNA change, and amino acid change. No publications were found based on this search. Due to the potential impact of frameshift variants and the lack of clarifying evidence, this variant is classified as a variant of unknown significance but suspicious for pathogenicity for this disease.

#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineunknownnot providednot providednot providednot providednot providednot providednot provided

From Labcorp Genetics (formerly Invitae), Labcorp, SCV003014846.2

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (1)

Description

This sequence change creates a premature translational stop signal (p.Thr171Serfs*148) in the CHST3 gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 309 amino acid(s) of the CHST3 protein. This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with CHST3-related conditions. This variant disrupts a region of the CHST3 protein in which other variant(s) (p.Leu286Trpfs*48) have been determined to be pathogenic (Invitae). This suggests that this is a clinically significant region of the protein, and that variants that disrupt it are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic.

#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineunknownnot providednot providednot providednot providednot providednot providednot provided

Last Updated: Sep 29, 2024