NM_000391.4(TPP1):c.1266G>C (p.Gln422His) AND not provided

Germline classification:: Pathogenic (2 submissions)
Last evaluated:: Dec 20, 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:: RCV000189782.10

Allele description [Variation Report for NM_000391.4(TPP1):c.1266G>C (p.Gln422His)]

NM_000391.4(TPP1):c.1266G>C (p.Gln422His)

Gene:

TPP1:tripeptidyl peptidase 1 [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

11p15.4

Genomic location:

Preferred name:

NM_000391.4(TPP1):c.1266G>C (p.Gln422His)

Other names:

5271G>C; p.Q422H:CAG>CAC

HGVS:

NC_000011.10:g.6615442C>G
NG_008653.1:g.9020G>C
NM_000391.4:c.1266G>CMANE SELECT
NP_000382.3:p.Gln422His
LRG_830t1:c.1266G>C
LRG_830:g.9020G>C
LRG_830p1:p.Gln422His
NC_000011.9:g.6636673C>G
NM_000391.3:c.1266G>C
O14773:p.Gln422His

Protein change:

Q422H

Links:

UniProtKB: O14773#VAR_009610; UniProtKB/Swiss-Prot: VAR_009610; dbSNP: rs121908200

NCBI 1000 Genomes Browser:

rs121908200

Molecular consequence:

NM_000391.4:c.1266G>C - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Synonyms:: none provided
Identifiers:: MedGen: C3661900

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000243430	GeneDx	criteria provided, single submitter (GeneDx Variant Classification Process June 2021)	Pathogenic (Sep 11, 2022)	germline	clinical testing	Citation Link,
SCV000628896	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Dec 20, 2023)	germline	clinical testing	PubMed (7) [See all records that cite these PMIDs] 12376936, 22612257, 25356970, 10330339, 17576681, 9536098, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000243430

GeneDx

criteria provided, single submitter

(GeneDx Variant Classification Process June 2021)

Pathogenic
(Sep 11, 2022)

germline

clinical testing

Citation Link,

SCV000628896

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Pathogenic
(Dec 20, 2023)

germline

clinical testing

PubMed (7)
[See all records that cite these PMIDs]

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

Late infantile neuronal ceroid lipofuscinosis: quantitative description of the clinical course in patients with CLN2 mutations.

Steinfeld R, Heim P, von Gregory H, Meyer K, Ullrich K, Goebel HH, Kohlschütter A.

Am J Med Genet. 2002 Nov 1;112(4):347-54.

PubMed [citation]

PMID:: 12376936

Targeted next generation sequencing as a diagnostic tool in epileptic disorders.

Lemke JR, Riesch E, Scheurenbrand T, Schubach M, Wilhelm C, Steiner I, Hansen J, Courage C, Gallati S, Bürki S, Strozzi S, Simonetti BG, Grunt S, Steinlin M, Alber M, Wolff M, Klopstock T, Prott EC, Lorenz R, Spaich C, Rona S, Lakshminarasimhan M, et al.

Epilepsia. 2012 Aug;53(8):1387-98. doi: 10.1111/j.1528-1167.2012.03516.x. Epub 2012 May 21.

PubMed [citation]

PMID:: 22612257

See all PubMed Citations (7)

Details of each submission

From GeneDx, SCV000243430.13

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

Description

Published functional studies demonstrate a damaging effect by decreased or zero activity versus wild type (Steinfeld R et al., 2004; Walus M et al., 2010); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis suggests this variant may impact gene splicing. In the absence of RNA/functional studies, the actual effect of this sequence change is unknown.; In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 25356970, 26795593, 20340139, 19038966, 10330339, 12376936, 29655203, 15317752, 22612257)

#	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

From Labcorp Genetics (formerly Invitae), Labcorp, SCV000628896.6

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (7)

Description

This sequence change replaces glutamine, which is neutral and polar, with histidine, which is basic and polar, at codon 422 of the TPP1 protein (p.Gln422His). This variant also falls at the last nucleotide of exon 10, which is part of the consensus splice site for this exon. This variant is present in population databases (rs121908200, gnomAD 0.006%). This missense change has been observed in individual(s) with late infantile neuronal ceroid lipofuscinosis (LINCL) (PMID: 10330339, 12376936, 22612257, 25356970). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 68738). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. Experimental studies have shown that this missense change affects TPP1 function (PMID: 10330339). Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic.

#	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: Sep 29, 2024

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