NM_001100913.3(PACS2):c.625G>A (p.Glu209Lys) AND not provided

This record was updated by the submitter. Please see the current version.

Germline classification:: Pathogenic (8 submissions)
Last evaluated:: Jan 22, 2024
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:: RCV000782018.43

Allele description

NM_001100913.3(PACS2):c.625G>A (p.Glu209Lys)

Gene:

PACS2:phosphofurin acidic cluster sorting protein 2 [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

14q32.33

Genomic location:

Preferred name:

NM_001100913.3(PACS2):c.625G>A (p.Glu209Lys)

Other names:

p.Glu209Lys

HGVS:

NC_000014.9:g.105368112G>A
NM_001100913.3:c.625G>AMANE SELECT
NM_001243127.3:c.424G>A
NM_015197.4:c.625G>A
NP_001094383.2:p.Glu209Lys
NP_001230056.1:p.Glu142Lys
NP_056012.2:p.Glu209Lys
NC_000014.8:g.105834449G>A
NM_001100913.2:c.625G>A
NM_001243127.3:c.424G>A
NM_015197.4:c.625G>A

Protein change:

E142K; GLU209LYS

Links:

OMIM: 610423.0001; dbSNP: rs1555408401

NCBI 1000 Genomes Browser:

rs1555408401

Molecular consequence:

NM_001100913.3:c.625G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001243127.3:c.424G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_015197.4:c.625G>A - missense variant - [Sequence Ontology: SO:0001583]

Observations:

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
SCV000920482	Laboratory of Molecular Genetics (Pr. Bezieau's lab), CHU de Nantes	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Aug 6, 2019)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV001248885	CeGaT Center for Human Genetics Tuebingen	criteria provided, single submitter (CeGaT Center For Human Genetics Tuebingen Variant Classification Criteria Version 2)	Pathogenic (Nov 1, 2023)	germline	clinical testing	Citation Link,
SCV001575671	Invitae	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Jan 22, 2024)	germline	clinical testing	PubMed (2) [See all records that cite these PMIDs] 29656858, 28492532
SCV001873688	GeneDx	criteria provided, single submitter (GeneDx Variant Classification Process June 2021)	Pathogenic (Feb 16, 2022)	germline	clinical testing	Citation Link,
SCV002051701	Greenwood Genetic Center Diagnostic Laboratories, Greenwood Genetic Center	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Jan 20, 2021)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV002501130	AiLife Diagnostics, AiLife Diagnostics	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Apr 29, 2020)	de novo	clinical testing	PubMed (10) [See all records that cite these PMIDs] 28628100, 31231135, 28191890, 31036916, 28867141, 30904718, 28135719, 29656858, 30290155, 25741868
SCV002818256	Al Jalila Children’s Genomics Center, Al Jalila Childrens Speciality Hospital	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Dec 17, 2022)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV004223968	Mayo Clinic Laboratories, Mayo Clinic	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Jul 29, 2022)	germline	clinical testing	PubMed (4) [See all records that cite these PMIDs] 29656858, 32416568, 33243487, 25741868

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	yes	17	not provided	not provided	not provided	not provided	clinical testing
not provided	germline	unknown	1	not provided	not provided	not provided	not provided	clinical testing
not provided	de novo	yes	1	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

Sherloc: a comprehensive refinement of the ACMG-AMP variant classification criteria.

Nykamp K, Anderson M, Powers M, Garcia J, Herrera B, Ho YY, Kobayashi Y, Patil N, Thusberg J, Westbrook M; Invitae Clinical Genomics Group., Topper S.

Genet Med. 2017 Oct;19(10):1105-1117. doi: 10.1038/gim.2017.37. Epub 2017 May 11. Erratum in: Genet Med. 2020 Jan;22(1):240. doi: 10.1038/s41436-019-0624-9.

PubMed [citation]

PMID:: 28492532
PMCID:: PMC5632818

Hotspots of missense mutation identify neurodevelopmental disorder genes and functional domains.

Geisheker MR, Heymann G, Wang T, Coe BP, Turner TN, Stessman HAF, Hoekzema K, Kvarnung M, Shaw M, Friend K, Liebelt J, Barnett C, Thompson EM, Haan E, Guo H, Anderlid BM, Nordgren A, Lindstrand A, Vandeweyer G, Alberti A, Avola E, Vinci M, et al.

Nat Neurosci. 2017 Aug;20(8):1043-1051. doi: 10.1038/nn.4589. Epub 2017 Jun 19.

PubMed [citation]

PMID:: 28628100
PMCID:: PMC5539915

See all PubMed Citations (13)

Details of each submission

From Laboratory of Molecular Genetics (Pr. Bezieau's lab), CHU de Nantes, SCV000920482.2

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

From CeGaT Center for Human Genetics Tuebingen, SCV001248885.24

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	15	not provided	not provided	clinical testing	not provided

Description

PACS2: PS2:Very Strong, PM2, PS4:Moderate, PS3:Supporting

#	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		15	not provided	not provided	not provided

From Invitae, SCV001575671.4

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

Description

This sequence change replaces glutamic acid, which is acidic and polar, with lysine, which is basic and polar, at codon 209 of the PACS2 protein (p.Glu209Lys). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with PACS2-related conditions (PMID: 29656858). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 495141). 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. 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

From GeneDx, SCV001873688.3

#	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 an impaired interaction between PACS2 and related proteins (Olson et al., 2018); Not observed at significant frequency in large population cohorts (gnomAD); 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: 28628100, 29656858, 28867141, 28135719, 30684285, 32416568, 32166392, 28191890, 30290155, 30904718, 31231135, 31036916, 25741868, 31130284, 34489640, 33243487, 33240318, 33461828, 33004838)

#	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 Greenwood Genetic Center Diagnostic Laboratories, Greenwood Genetic Center, SCV002051701.2

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

Description

PS2_very_strong, PS3, PS4, PM2

#	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 AiLife Diagnostics, AiLife Diagnostics, SCV002501130.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	1	not provided	not provided	clinical testing	PubMed (10)

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

From Al Jalila Children’s Genomics Center, Al Jalila Childrens Speciality Hospital, SCV002818256.1

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

From Mayo Clinic Laboratories, Mayo Clinic, SCV004223968.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	1	not provided	not provided	clinical testing	PubMed (4)

Description

BP4, PM2, PS2_very_strong, PS4

#	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		1	not provided	not provided	not provided

Last Updated: Aug 4, 2024

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