NM_001614.5(ACTG1):c.983A>G (p.Lys328Arg) AND multiple conditions

Germline classification:: Conflicting interpretations of pathogenicity (2 submissions)
Last evaluated:: Jul 5, 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:: RCV003804728.3

Allele description [Variation Report for NM_001614.5(ACTG1):c.983A>G (p.Lys328Arg)]

NM_001614.5(ACTG1):c.983A>G (p.Lys328Arg)

Gene:

ACTG1:actin gamma 1 [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

17q25.3

Genomic location:

Preferred name:

NM_001614.5(ACTG1):c.983A>G (p.Lys328Arg)

HGVS:

NC_000017.11:g.81510928T>C
NG_011433.1:g.6874A>G
NG_015964.2:g.868T>C
NM_001199954.3:c.983A>G
NM_001614.5:c.983A>GMANE SELECT
NP_001186883.1:p.Lys328Arg
NP_001605.1:p.Lys328Arg
NC_000017.10:g.79477954T>C
NR_037688.3:n.1055A>G

Protein change:

K328R

Molecular consequence:

NM_001199954.3:c.983A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001614.5:c.983A>G - missense variant - [Sequence Ontology: SO:0001583]
NR_037688.3:n.1055A>G - non-coding transcript variant - [Sequence Ontology: SO:0001619]

Condition(s)

Name:: Autosomal dominant nonsyndromic hearing loss 20
Synonyms:: Deafness, autosomal dominant 20
Identifiers:: MONDO: MONDO:0011480; MedGen: C1858172; Orphanet: 90635; OMIM: 604717

Name:: Baraitser-winter syndrome 2
Identifiers:: MONDO: MONDO:0013812; MedGen: C3281235; Orphanet: 2995; OMIM: 614583

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV004607558	Invitae	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Uncertain significance (Jul 5, 2023)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV004697700	Molecular Genetics Lab, CHRU Brest	criteria provided, single submitter (ACMG Guidelines, 2015)	Likely pathogenic	de novo	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

SCV004607558

Invitae

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Uncertain significance
(Jul 5, 2023)

germline

clinical testing

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

SCV004697700

Molecular Genetics Lab, CHRU Brest

criteria provided, single submitter

(ACMG Guidelines, 2015)

Likely pathogenic

de novo

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	de novo	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

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

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 Invitae, SCV004607558.1

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

Description

This sequence change replaces lysine, which is basic and polar, with arginine, which is basic and polar, at codon 328 of the ACTG1 protein (p.Lys328Arg). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with ACTG1-related conditions. 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 tolerated. 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 Molecular Genetics Lab, CHRU Brest, SCV004697700.1

#	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	de novo	yes	not provided	not provided	not provided		not provided	not provided	not provided	not provided

Last Updated: Jun 23, 2024

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