NM_004917.5(KLK4):c.458G>A (p.Trp153Ter) AND Amelogenesis imperfecta type 2A1

Germline classification:: Likely pathogenic (2 submissions)
Last evaluated:: Mar 25, 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:: RCV000006452.5

Allele description [Variation Report for NM_004917.5(KLK4):c.458G>A (p.Trp153Ter)]

NM_004917.5(KLK4):c.458G>A (p.Trp153Ter)

Gene:

KLK4:kallikrein related peptidase 4 [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

19q13.41

Genomic location:

Preferred name:

NM_004917.5(KLK4):c.458G>A (p.Trp153Ter)

HGVS:

NC_000019.10:g.50908596C>T
NG_012154.2:g.7143G>A
NM_001302961.2:c.173G>A
NM_004917.3:c.458G>A
NM_004917.5:c.458G>AMANE SELECT
NP_001289890.1:p.Trp58Ter
NP_004908.4:p.Trp153Ter
NC_000019.9:g.51411852C>T
NR_126566.2:n.451G>A

Protein change:

W153*; TRP153TER

Links:

OMIM: 603767.0001; dbSNP: rs104894704

NCBI 1000 Genomes Browser:

rs104894704

Molecular consequence:

NR_126566.2:n.451G>A - non-coding transcript variant - [Sequence Ontology: SO:0001619]
NM_001302961.2:c.173G>A - nonsense - [Sequence Ontology: SO:0001587]
NM_004917.5:c.458G>A - nonsense - [Sequence Ontology: SO:0001587]

Condition(s)

Name:: Amelogenesis imperfecta type 2A1
Synonyms:: AMELOGENESIS IMPERFECTA, PIGMENTED HYPOMATURATION TYPE, 1; Amelogenesis imperfecta, hypomaturation type, IIA1; Amelogenesis imperfecta, type IIA1
Identifiers:: MONDO: MONDO:0008772; MedGen: C2673922; Orphanet: 88661; OMIM: 204700

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000026635	OMIM	no assertion criteria provided	Pathogenic (Jan 1, 2011)	germline	literature only	PubMed (2) [See all records that cite these PMIDs] 15235027, 21597265
SCV004847469	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	criteria provided, single submitter (ACMG Guidelines, 2015)	Likely Pathogenic (Mar 25, 2024)	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

SCV000026635

OMIM

no assertion criteria provided

Pathogenic
(Jan 1, 2011)

germline

literature only

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

SCV004847469

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

criteria provided, single submitter

(ACMG Guidelines, 2015)

Likely Pathogenic
(Mar 25, 2024)

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	not provided	not provided	not provided	not provided	not provided	not provided	literature only
not provided	germline	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

Mutation in kallikrein 4 causes autosomal recessive hypomaturation amelogenesis imperfecta.

Hart PS, Hart TC, Michalec MD, Ryu OH, Simmons D, Hong S, Wright JT.

J Med Genet. 2004 Jul;41(7):545-9. No abstract available.

PubMed [citation]

PMID:: 15235027
PMCID:: PMC1735847

Amelogenesis imperfecta: genotype-phenotype studies in 71 families.

Wright JT, Torain M, Long K, Seow K, Crawford P, Aldred MJ, Hart PS, Hart TC.

Cells Tissues Organs. 2011;194(2-4):279-83. doi: 10.1159/000324339. Epub 2011 May 19.

PubMed [citation]

PMID:: 21597265
PMCID:: PMC3178091

See all PubMed Citations (3)

Details of each submission

From OMIM, SCV000026635.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	literature only	PubMed (2)

Description

In 2 African American sibs with autosomal recessive pigmented hypomaturation-type amelogenesis imperfecta (AI2A1; 204700), Hart et al. (2004) identified a homozygous c.458G-A transition in the KLK4 gene, resulting in a trp153-to-ter (W153X) nonsense mutation at a highly conserved residue. The truncated protein would lack the final 101 amino acids, including serine-107 of the catalytic triad. The mutation was not found in 134 African American control chromosomes. Wright et al. (2011) identified the same mutation in 2 affected members of an unrelated African American family with amelogenesis imperfecta.

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

From Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine, SCV004847469.1

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

Description

The p.Trp153X variant in KLK4 has been reported in 2 homozygous individuals with amelogenesis imperfecta and segregated with disease in at least 1 affected relative from 1 family (Hart 2004 PMID: 15235027, Wright 2011 PMID: 21597265). This variant has also been reported by other clinical laboratories in ClinVar (Variation ID 6079) and has been identified in 0.22% (92/41468) of African/African American chromosomes by gnomAD (http://gnomad.broadinstitute.org, v4.0.0). This nonsense variant leads to a premature termination codon at position 153, which is predicted to lead to a truncated or absent protein. Loss of function variants in the KLK4 gene have been reported in individuals with autosomal recessive amelogenesis imperfecta (Wang 2013 PMID: 23355523, Seymen 2015 PMID: 26124219, Smith 2017 PMID: 28611678, Lee 2022 PMID: 35207639). Additionally, studies have shown that KLK4 null mice had defective enamel, recapitulating features of the human phenotype (Simmer 2009 PubMed: 19578120, Nunez 2016 PMID: 26620968). In summary, although additional studies are required to fully establish its clinical significance, this variant meets criteria to be classified as likely pathogenic for autosomal recessive amelogenesis imperfecta. ACMG/AMP Criteria applied: PVS1, PM3.

#	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

Last Updated: Oct 8, 2024

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