NM_001083116.3(PRF1):c.1620A>G (p.Gln540=) AND not provided

Germline classification:: Conflicting interpretations of pathogenicity (3 submissions)
Last evaluated:: Jan 1, 2024
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:: RCV001358428.12

Allele description [Variation Report for NM_001083116.3(PRF1):c.1620A>G (p.Gln540=)]

NM_001083116.3(PRF1):c.1620A>G (p.Gln540=)

Gene:

PRF1:perforin 1 [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

10q22.1

Genomic location:

Preferred name:

NM_001083116.3(PRF1):c.1620A>G (p.Gln540=)

HGVS:

NC_000010.11:g.70598101T>C
NG_009615.1:g.9675A>G
NM_001083116.3:c.1620A>GMANE SELECT
NM_005041.6:c.1620A>G
NP_001076585.1:p.Gln540=
NP_005032.2:p.Gln540=
LRG_94t1:c.1620A>G
LRG_94:g.9675A>G
NC_000010.10:g.72357857T>C
NM_001083116.1:c.1620A>G
NM_005041.4:c.1620A>G

Links:

dbSNP: rs149776121

NCBI 1000 Genomes Browser:

rs149776121

Molecular consequence:

NM_001083116.3:c.1620A>G - synonymous variant - [Sequence Ontology: SO:0001819]
NM_005041.6:c.1620A>G - synonymous variant - [Sequence Ontology: SO:0001819]

Observations:

Condition(s)

Synonyms:: none provided
Identifiers:: MedGen: C3661900

Recent activity

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PREDICTED: Mus musculus tumor necrosis factor receptor superfamily, member 23 (T...
PREDICTED: Mus musculus tumor necrosis factor receptor superfamily, member 23 (Tnfrsf23), transcript variant X5, misc_RNA
gi|1907185138|ref|XR_004934224.1|

Nucleotide
Mus musculus tumor necrosis factor receptor superfamily, member 23 (Tnfrsf23), t...
Mus musculus tumor necrosis factor receptor superfamily, member 23 (Tnfrsf23), transcript variant 3, non-coding RNA
gi|815729616|ref|NR_131763.1|

Nucleotide
Mus musculus tumor necrosis factor receptor superfamily, member 23 (Tnfrsf23), t...
Mus musculus tumor necrosis factor receptor superfamily, member 23 (Tnfrsf23), transcript variant 1, mRNA
gi|809281450|ref|NM_024290.4|

Nucleotide

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV001554157	Department of Pathology and Laboratory Medicine, Sinai Health System - The Canadian Open Genetics Repository (COGR) See additional submitters Franklin by Genoox	no assertion criteria provided	Uncertain significance	unknown	clinical testing
SCV002009737	Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden	criteria provided, single submitter (ACMG Guidelines, 2015)	Uncertain significance (Nov 3, 2021)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV004126686	CeGaT Center for Human Genetics Tuebingen	criteria provided, single submitter (CeGaT Center For Human Genetics Tuebingen Variant Classification Criteria Version 2)	Likely benign (Jan 1, 2024)	germline	clinical testing	Citation Link

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV001554157

Department of Pathology and Laboratory Medicine, Sinai Health System - The Canadian Open Genetics Repository (COGR)

See additional submitters

no assertion criteria provided

Uncertain significance

unknown

clinical testing

SCV002009737

Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden

criteria provided, single submitter

(ACMG Guidelines, 2015)

Uncertain significance
(Nov 3, 2021)

germline

clinical testing

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

SCV004126686

CeGaT Center for Human Genetics Tuebingen

criteria provided, single submitter

(CeGaT Center For Human Genetics Tuebingen Variant Classification Criteria Version 2)

Likely benign
(Jan 1, 2024)

germline

clinical testing

Citation Link

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	yes	2	not provided	not provided	not provided	not provided	clinical testing
not provided	unknown	yes	not provided	not provided	not provided	not provided	not provided	clinical testing
not provided	germline	not provided	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

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 Department of Pathology and Laboratory Medicine, Sinai Health System - The Canadian Open Genetics Repository (COGR), SCV001554157.1

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

Description

The PRF1 p.Gln540Gln variant was identified in one homozygous individual with multiple sclerosis and one heterozygous individual with familial hemophagocytic lymphohistiocytosis (Cappellano_2008_PMID:18496551, Liu_2015_PMID:26274329). The variant was identified in dbSNP (ID: rs149776121), ClinVar (classified as benign by Invitae) and LOVD 3.0 (variant effect not shared), but was not identified in Cosmic. The variant was identified in control databases in 499 of 268182 chromosomes (1 homozygous) at a frequency of 0.001861 increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Database March 6, 2019, v2.1.1, non-cancer). The variant was observed in the following populations: East Asian in 245 of 19248 chromosomes (freq: 0.01273), European (Finnish) in 81 of 25022 chromosomes (freq: 0.003237), South Asian in 76 of 30526 chromosomes (freq: 0.00249), Other in 11 of 6702 chromosomes (freq: 0.001641), European (non-Finnish) in 76 of 118130 chromosomes (freq: 0.000643), Latino in 6 of 35106 chromosomes (freq: 0.000171), African in 3 of 23586 chromosomes (freq: 0.000127) and Ashkenazi Jewish in 1 of 9862 chromosomes (freq: 0.000101). The p.Gln540Gln variant is not expected to have clinical significance because it does not result in a change of amino acid and is not located in a known consensus splice site. However, 4 of 4 in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) predict a greater than 10% difference in splicing and the creation of a new 3' splice site. However, this has not been confirmed by RNA analysis and is not predictive enough to assume pathogenicity. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of uncertain significance.

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

From Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden, SCV002009737.3

#	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	germline	not provided	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From CeGaT Center for Human Genetics Tuebingen, SCV004126686.8

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	2	not provided	not provided	clinical testing	not provided

Description

PRF1: BP4, BP7, BS1

#	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		2	not provided	not provided	not provided

Last Updated: Aug 4, 2024

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