NM_014140.3(SMARCAL1):c.2225C>T (p.Thr742Met) AND Schimke immuno-osseous dysplasia

Clinical significance:Uncertain significance (Last evaluated: Aug 7, 2019)

Review status:2 stars out of maximum of 4 stars

criteria provided, multiple submitters, no conflicts

Based on:
3 submissions [Details]
Record status:
current
Accession:
RCV000548531.5

Allele description [Variation Report for NM_014140.3(SMARCAL1):c.2225C>T (p.Thr742Met)]

NM_014140.3(SMARCAL1):c.2225C>T (p.Thr742Met)

Gene:
SMARCAL1:SWI/SNF related, matrix associated, actin dependent regulator of chromatin, subfamily a like 1 [Gene - OMIM - HGNC]
Variant type:
single nucleotide variant
Cytogenetic location:
2q35
Genomic location:
Preferred name:
NM_014140.3(SMARCAL1):c.2225C>T (p.Thr742Met)
HGVS:
  • NC_000002.12:g.216468027C>T
  • NG_009771.1:g.60614C>T
  • NM_001127207.2:c.2225C>T
  • NM_014140.3:c.2225C>T
  • NP_001120679.1:p.Thr742Met
  • NP_054859.2:p.Thr742Met
  • LRG_108t1:c.2225C>T
  • LRG_108:g.60614C>T
  • LRG_108p1:p.Thr742Met
  • NC_000002.11:g.217332750C>T
Protein change:
T742M
Links:
dbSNP: rs2271336
NCBI 1000 Genomes Browser:
rs2271336
Molecular consequence:
  • NM_001127207.2:c.2225C>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_014140.3:c.2225C>T - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Name:
Schimke immuno-osseous dysplasia (SIOD)
Synonyms:
Spondyloepiphyseal dysplasia nephrotic syndrome; Schimke syndrome; Schimke immunoosseous dysplasia
Identifiers:
MONDO: MONDO:0009458; MedGen: C0877024; Orphanet: 1830; OMIM: 242900

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Assertion and evidence details

Submission AccessionSubmitterReview Status
(Assertion method)
Clinical Significance
(Last evaluated)
OriginMethodCitations
SCV000636844Invitaecriteria provided, single submitter
Uncertain significance
(Aug 7, 2019)
germlineclinical testing

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

SCV001299924Illumina Clinical Services Laboratory,Illuminacriteria provided, single submitter
Uncertain significance
(Jan 13, 2018)
germlineclinical testing

Citation Link,

SCV001455767Natera, Inc.no assertion criteria providedUncertain significance
(Sep 16, 2020)
germlineclinical testing

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):240-242.

PubMed [citation]
PMID:
28492532
PMCID:
PMC5632818

Details of each submission

From Invitae, SCV000636844.3

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

Description

This sequence change replaces threonine with methionine at codon 742 of the SMARCAL1 protein (p.Thr742Met). The threonine residue is weakly conserved and there is a moderate physicochemical difference between threonine and methionine. This variant is present in population databases (rs2271336, ExAC 0.04%). This variant has not been reported in the literature in individuals with SMARCAL1-related disease. ClinVar contains an entry for this variant (Variation ID: 463147). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.

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

From Illumina Clinical Services Laboratory,Illumina, SCV001299924.1

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

Description

This variant was observed in the ICSL laboratory 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, this variant 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, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease.

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

From Natera, Inc., SCV001455767.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testingnot provided
#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineunknownnot providednot providednot providednot providednot providednot providednot provided

Last Updated: Aug 27, 2021

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