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NM_000359.3(TGM1):c.1186C>T (p.Arg396Cys) AND Lamellar ichthyosis

Germline classification:
Likely pathogenic (1 submission)
Last evaluated:
Mar 8, 2024
Review status:
1 star out of maximum of 4 stars
criteria provided, single submitter
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:
RCV004576967.2

Allele description [Variation Report for NM_000359.3(TGM1):c.1186C>T (p.Arg396Cys)]

NM_000359.3(TGM1):c.1186C>T (p.Arg396Cys)

Gene:
TGM1:transglutaminase 1 [Gene - OMIM - HGNC]
Variant type:
single nucleotide variant
Cytogenetic location:
14q12
Genomic location:
Preferred name:
NM_000359.3(TGM1):c.1186C>T (p.Arg396Cys)
HGVS:
  • NC_000014.9:g.24258647G>A
  • NG_007150.1:g.9520C>T
  • NM_000359.3:c.1186C>TMANE SELECT
  • NP_000350.1:p.Arg396Cys
  • NC_000014.8:g.24727853G>A
  • NM_000359.2:c.1186C>T
  • NM_000359.2:c.[1186C>T]
Protein change:
R396C
Links:
dbSNP: rs543521135
NCBI 1000 Genomes Browser:
rs543521135
Molecular consequence:
  • NM_000359.3:c.1186C>T - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Name:
Lamellar ichthyosis
Identifiers:
MONDO: MONDO:0017778; MedGen: C5848247

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Assertion and evidence details

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Submission AccessionSubmitterReview Status
(Assertion method)		Clinical Significance
(Last evaluated)		OriginMethodCitations
SCV002051227Women's Health and Genetics/Laboratory Corporation of America, LabCorp
criteria provided, single submitter

(LabCorp Variant Classification Summary - May 2015)		Likely pathogenic
(Mar 8, 2024) 		germlineclinical testing

PubMed (2)
[See all records that cite these PMIDs]

Citation Link

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Summary from all submissions

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

Citations

PubMed

Molecular profiling of lamellar ichthyosis pathogenic missense mutations on the structural and stability aspects of TGM1 protein.

Nasser KK, Banaganapalli B, Shinawi T, Elango R, Shaik NA.

J Biomol Struct Dyn. 2021 Sep;39(14):4962-4972. doi: 10.1080/07391102.2020.1782770. Epub 2020 Jun 29.

PubMed [citation]
PMID:
32597326

Autosomal recessive congenital ichthyosis: Genomic landscape and phenotypic spectrum in a cohort of 125 consanguineous families.

Youssefian L, Vahidnezhad H, Saeidian AH, Touati A, Sotoudeh S, Mahmoudi H, Mansouri P, Daneshpazhooh M, Aghazadeh N, Hesari KK, Basiri M, Londin E, Kumar G, Zeinali S, Fortina P, Uitto J.

Hum Mutat. 2019 Mar;40(3):288-298. doi: 10.1002/humu.23695. Epub 2019 Jan 16.

PubMed [citation]
PMID:
30578701

Details of each submission

From Women's Health and Genetics/Laboratory Corporation of America, LabCorp, SCV002051227.4

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (2)

Description

Variant summary: TGM1 c.1186C>T (p.Arg396Cys) results in a non-conservative amino acid change located in the Transglutaminase-like domain (IPR002931) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. A recent study using structural modeling, molecular docking and molecular dynamics approaches concluded that missense variants in the Transglut_core domain of TGM1 are deleterious to the stability and structural changes of the TGM1 protein (Nasser_2020). The variant allele was found at a frequency of 8e-06 in 251310 control chromosomes. c.1186C>T has been reported in the literature as a homozygous genotype in at-least one individual from a consanguineous union affected with Lamellar Ichthyosis (example, Youssefian_2019). These data indicate that the variant may be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 32597326, 30578701). ClinVar contains an entry for this variant (Variation ID: 633787). Based on the evidence outlined above, the variant was classified as likely pathogenic.

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

Last Updated: Nov 24, 2024