NM_014363.6(SACS):c.8793dup (p.Arg2932fs) AND not provided

Germline classification:: Pathogenic (2 submissions)
Last evaluated:: Sep 8, 2020
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:: RCV001288377.6

Allele description [Variation Report for NM_014363.6(SACS):c.8793dup (p.Arg2932fs)]

NM_014363.6(SACS):c.8793dup (p.Arg2932fs)

Gene:

SACS:sacsin molecular chaperone [Gene - OMIM - HGNC]

Variant type:

Duplication

Cytogenetic location:

13q12.12

Genomic location:

Preferred name:

NM_014363.6(SACS):c.8793dup (p.Arg2932fs)

HGVS:

NC_000013.11:g.23335089dup
NG_012342.1:g.103620dup
NM_001278055.2:c.8352dup
NM_014363.6:c.8793dupMANE SELECT
NP_001264984.1:p.Arg2785fs
NP_055178.3:p.Arg2932fs
NC_000013.10:g.23909221_23909222insT
NC_000013.10:g.23909228dup
NM_014363.4:c.8793dup
NM_014363.5:c.8793dup
NM_014363.5:c.8793dupA

Protein change:

R2785fs

Links:

dbSNP: rs767871841

NCBI 1000 Genomes Browser:

rs767871841

Molecular consequence:

NM_001278055.2:c.8352dup - frameshift variant - [Sequence Ontology: SO:0001589]
NM_014363.6:c.8793dup - frameshift variant - [Sequence Ontology: SO:0001589]

Condition(s)

Synonyms:: none provided
Identifiers:: MedGen: C3661900

Recent activity

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Rattus norvegicus syntrophin, alpha 1 (Snta1), mRNA
Rattus norvegicus syntrophin, alpha 1 (Snta1), mRNA
gi|201023316|ref|NM_001100901.1|

Nucleotide
Rattus norvegicus syntrophin, acidic 1, mRNA (cDNA clone IMAGE:7370211), partial...
Rattus norvegicus syntrophin, acidic 1, mRNA (cDNA clone IMAGE:7370211), partial cds
gi|72679480|gb|BC100086.1|

Nucleotide

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV001475443	Athena Diagnostics	criteria provided, single submitter (Athena Diagnostics Criteria)	Pathogenic (Jun 10, 2020)	unknown	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV002064492	Genetic Services Laboratory, University of Chicago	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Sep 8, 2020)	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

SCV001475443

Athena Diagnostics

criteria provided, single submitter

(Athena Diagnostics Criteria)

Pathogenic
(Jun 10, 2020)

unknown

clinical testing

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

SCV002064492

Genetic Services Laboratory, University of Chicago

criteria provided, single submitter

(ACMG Guidelines, 2015)

Pathogenic
(Sep 8, 2020)

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	yes	not provided	not provided	not provided	not provided	not provided	clinical testing
not provided	unknown	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

A Standardized DNA Variant Scoring System for Pathogenicity Assessments in Mendelian Disorders.

Karbassi I, Maston GA, Love A, DiVincenzo C, Braastad CD, Elzinga CD, Bright AR, Previte D, Zhang K, Rowland CM, McCarthy M, Lapierre JL, Dubois F, Medeiros KA, Batish SD, Jones J, Liaquat K, Hoffman CA, Jaremko M, Wang Z, Sun W, Buller-Burckle A, et al.

Hum Mutat. 2016 Jan;37(1):127-34. doi: 10.1002/humu.22918. Epub 2015 Oct 29.

PubMed [citation]

PMID:: 26467025
PMCID:: PMC4737317

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 Athena Diagnostics, SCV001475443.1

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

Description

The variant results in a shift of the reading frame, and is therefore predicted to result in the loss of a functional protein. Found in at least one patient with expected phenotype for this gene, and found in general population data at a frequency that is consistent with pathogenicity.

#	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 Genetic Services Laboratory, University of Chicago, SCV002064492.1

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

Description

DNA sequence analysis of the SACS gene demonstrated a one base pair duplication in exon 10, c.8793dup. This sequence change results in an amino acid frameshift and creates a premature stop codon 7 amino acids downstream of the variant, p.Arg2932Thrfs*7. This sequence change is not predicted to result in nonsense mediated decay, but does disrupt the c-terminal domain of the SACS protein. This sequencing change has been described in the gnomAD database with a low overall population frequency of 0.001% and a frequency of 0.004% in the African sub group (dbSNP rs767871841). Other truncating variants within this region and downstream of this variant have been reported in patients with SACS-related disorders (PMIDs: 18465152, 15156359, 22816526). Collectively these evidences indicate that, this p.Arg2932Thrfs*7 sequence change is pathogenic.

#	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

Last Updated: Sep 29, 2024

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