NM_000310.4(PPT1):c.125G>A (p.Gly42Glu) AND Neuronal ceroid lipofuscinosis 1

Germline classification:: Conflicting interpretations of pathogenicity (4 submissions)
Last evaluated:: Jul 26, 2023
Review status:: criteria provided, conflicting classifications

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:: RCV000049590.7

Allele description [Variation Report for NM_000310.4(PPT1):c.125G>A (p.Gly42Glu)]

NM_000310.4(PPT1):c.125G>A (p.Gly42Glu)

Gene:

PPT1:palmitoyl-protein thioesterase 1 [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

1p34.2

Genomic location:

Preferred name:

NM_000310.4(PPT1):c.125G>A (p.Gly42Glu)

HGVS:

NC_000001.11:g.40092507C>T
NG_009192.1:g.9964G>A
NM_000310.4:c.125G>AMANE SELECT
NM_001142604.2:c.125-2995G>A
NM_001363695.2:c.125G>A
NP_000301.1:p.Gly42Glu
NP_000301.1:p.Gly42Glu
NP_001350624.1:p.Gly42Glu
LRG_690t1:c.125G>A
LRG_690:g.9964G>A
LRG_690p1:p.Gly42Glu
NC_000001.10:g.40558179C>T
NM_000310.3:c.125G>A
P50897:p.Gly42Glu

Protein change:

G42E

Links:

UniProtKB: P50897#VAR_005549; dbSNP: rs386833631

NCBI 1000 Genomes Browser:

rs386833631

Molecular consequence:

NM_001142604.2:c.125-2995G>A - intron variant - [Sequence Ontology: SO:0001627]
NM_000310.4:c.125G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001363695.2:c.125G>A - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Name:: Neuronal ceroid lipofuscinosis 1 (CLN1)
Synonyms:: CEROID LIPOFUSCINOSIS, NEURONAL, 1, VARIABLE AGE AT ONSET; CLN1 variable age at onset; Infantile CLN (type of CLN1); See all synonyms [MedGen]
Identifiers:: MONDO: MONDO:0009744; MedGen: C1850451; OMIM: 256730

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000081997	Juha Muilu Group; Institute for Molecular Medicine Finland (FIMM)	no assertion criteria provided	probable-pathogenic	not provided	not provided	PubMed (1) [See all records that cite this PMID]
SCV000220645	Counsyl	criteria provided, single submitter (Counsyl Autosomal and X-linked Recessive Disease Classification criteria (2015))	Likely pathogenic (Aug 28, 2014)	unknown	literature only	PubMed (8) [See all records that cite these PMIDs] 21990111, 11440996, 9664077, 19793631, 19440452, 21228398, 14997939, 11073228 Counsyl Autosomal and X-linked Recessive Disease Classification criteria (2015), Citation Link,
SCV003523270	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Uncertain significance (Sep 1, 2022)	germline	clinical testing	PubMed (3) [See all records that cite these PMIDs] 9664077, 11440996, 28492532
SCV004204148	Baylor Genetics	criteria provided, single submitter (ACMG Guidelines, 2015)	Likely pathogenic (Jul 26, 2023)	unknown	clinical testing	PubMed (1) [See all records that cite this PMID]

Description

FinDis database variant: This variant was not found or characterized by our laboratory, data were collected from public sources: see reference: SCV000081997

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing
not provided	not provided	not provided	not provided	not provided	not provided	1	not provided	literature only
not provided	unknown	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing, literature only

Citations

PubMed

Update of the mutation spectrum and clinical correlations of over 360 mutations in eight genes that underlie the neuronal ceroid lipofuscinoses.

Kousi M, Lehesjoki AE, Mole SE.

Hum Mutat. 2012 Jan;33(1):42-63. doi: 10.1002/humu.21624. Epub 2011 Nov 16. Review.

PubMed [citation]

PMID:: 21990111

Structural basis of neuronal ceroid lipofuscinosis 1.

Ohno K, Saito S, Sugawara K, Suzuki T, Togawa T, Sakuraba H.

Brain Dev. 2010 Aug;32(7):524-30. doi: 10.1016/j.braindev.2009.08.010. Epub 2009 Sep 29.

PubMed [citation]

PMID:: 19793631

See all PubMed Citations (10)

Details of each submission

From Juha Muilu Group; Institute for Molecular Medicine Finland (FIMM), SCV000081997.1

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

Description

Converted during submission to Likely pathogenic.

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

From Counsyl, SCV000220645.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	literature only	PubMed (8)

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

From Labcorp Genetics (formerly Invitae), Labcorp, SCV003523270.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (3)

Description

This sequence change replaces glycine, which is neutral and non-polar, with glutamic acid, which is acidic and polar, at codon 42 of the PPT1 protein (p.Gly42Glu). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with neuronal ceroid lipofuscinosis (PMID: 9664077). ClinVar contains an entry for this variant (Variation ID: 56179). 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 disruptive. Experimental studies have shown that this missense change affects PPT1 function (PMID: 11440996). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. 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.

#	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 Baylor Genetics, SCV004204148.1

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

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

Last Updated: Sep 29, 2024

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