NM_201631.4(TGM5):c.600G>C (p.Lys200Asn) AND Acral peeling skin syndrome

Germline classification:: Uncertain significance (2 submissions)
Last evaluated:: Jul 17, 2023
Review status:: 2 stars out of maximum of 4 stars
criteria provided, multiple submitters, no conflicts

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:: RCV001120598.5

Allele description [Variation Report for NM_201631.4(TGM5):c.600G>C (p.Lys200Asn)]

NM_201631.4(TGM5):c.600G>C (p.Lys200Asn)

Gene:

TGM5:transglutaminase 5 [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

15q15.2

Genomic location:

Preferred name:

NM_201631.4(TGM5):c.600G>C (p.Lys200Asn)

HGVS:

NC_000015.10:g.43253590C>G
NG_016124.1:g.18268G>C
NM_004245.4:c.354G>C
NM_201631.4:c.600G>CMANE SELECT
NP_004236.1:p.Lys118Asn
NP_963925.2:p.Lys200Asn
NC_000015.9:g.43545788C>G
NM_201631.3:c.600G>C

Protein change:

K118N

Links:

dbSNP: rs758206600

NCBI 1000 Genomes Browser:

rs758206600

Molecular consequence:

NM_004245.4:c.354G>C - missense variant - [Sequence Ontology: SO:0001583]
NM_201631.4:c.600G>C - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Name:: Acral peeling skin syndrome
Synonyms:: Peeling skin syndrome, acral type (subtype); Peeling skin syndrome 2
Identifiers:: MONDO: MONDO:0012345; MedGen: C1853354; Orphanet: 263534; OMIM: 609796

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV001279094	Illumina Laboratory Services, Illumina	criteria provided, single submitter (ICSL Variant Classification Criteria 13 December 2019)	Uncertain significance (Apr 27, 2017)	germline	clinical testing	PubMed (1) [See all records that cite this PMID] Citation Link,
SCV005085976	Victorian Clinical Genetics Services, Murdoch Childrens Research Institute See additional submitters Shariant Australia, Australian Genomics	criteria provided, single submitter (ACMG Guidelines, 2015)	Uncertain significance (Jul 17, 2023)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV001279094

Illumina Laboratory Services, Illumina

criteria provided, single submitter

(ICSL Variant Classification Criteria 13 December 2019)

Uncertain significance
(Apr 27, 2017)

germline

clinical testing

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

Citation Link,

SCV005085976

Victorian Clinical Genetics Services, Murdoch Childrens Research Institute

See additional submitters

criteria provided, single submitter

(ACMG Guidelines, 2015)

Uncertain significance
(Jul 17, 2023)

germline

clinical testing

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

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	yes	not provided	not provided	not provided	not provided	not provided	clinical testing
not provided	germline	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

[Evolutionary-biological peculiarities of transglutaminase. Structure, physiological functions, application].

Shleĭkin AG, Danilov NP.

Zh Evol Biokhim Fiziol. 2011 Jan-Feb;47(1):3-14. Review. Russian.

PubMed [citation]

PMID:: 21469335

Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology.

Richards S, Aziz N, Bale S, Bick D, Das S, Gastier-Foster J, Grody WW, Hegde M, Lyon E, Spector E, Voelkerding K, Rehm HL; ACMG Laboratory Quality Assurance Committee..

Genet Med. 2015 May;17(5):405-24. doi: 10.1038/gim.2015.30. Epub 2015 Mar 5.

PubMed [citation]

PMID:: 25741868
PMCID:: PMC4544753

Details of each submission

From Illumina Laboratory Services, Illumina, SCV001279094.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (1)

Description

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Victorian Clinical Genetics Services, Murdoch Childrens Research Institute, SCV005085976.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (1)

Description

Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as VUS-3B. Following criteria are met: 0102 - Loss-of-function is a known mechanism of disease for this gene and is associated with peeling skin syndrome 2 (MIM#609796). (I) 0106 - This gene is associated with autosomal recessive disease. (I) 0200 - Variant is predicted to result in a missense amino acid change from lysine to asparagine. (I) 0251 - This variant is heterozygous. (I) 0304 - Variant is present in gnomAD (v2) <0.01 for a recessive condition (1 heterozygote, 0 homozygotes). (SP) 0502 - Missense variant with conflicting in silico predictions and uninformative conservation. (I) 0604 - Variant is not located in an established domain, motif, hotspot or informative constraint region. (I) 0705 - No comparable missense variants have previous evidence for pathogenicity. (I) 0809 - Previous evidence of pathogenicity for this variant is inconclusive. This variant has been classified as a VUS by a clinical laboratory in ClinVar who observed it in an unaffected individual. (I) 0905 - No published segregation evidence has been identified for this variant. (I) 1007 - No published functional evidence has been identified for this variant. (I) 1201 - Heterozygous variant detected in trans with a second pathogenic heterozygous variant (NM_201631.3(TGM5):c.337G>T; p.(Gly113Cys)) in a recessive disease. In addition, it was shown in cis with another VUS (NM_201631.3(TGM5):c.1020T>A; p.(Asn340Lys)). (I) 1205 - This variant has been shown to be maternally inherited (by segregation analysis). (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	yes	not provided	not provided	not provided		not provided	not provided	not provided	not provided

Last Updated: Aug 4, 2024

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