NM_001614.5(ACTG1):c.848T>C (p.Met283Thr) AND Autosomal dominant nonsyndromic hearing loss 20

Germline classification:: Likely pathogenic (2 submissions)
Last evaluated:: Feb 28, 2023
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:: RCV002052085.2

Allele description [Variation Report for NM_001614.5(ACTG1):c.848T>C (p.Met283Thr)]

NM_001614.5(ACTG1):c.848T>C (p.Met283Thr)

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.848T>C (p.Met283Thr)

HGVS:

NC_000017.11:g.81511063A>G
NG_011433.1:g.6739T>C
NM_001199954.3:c.848T>C
NM_001614.5:c.848T>CMANE SELECT
NP_001186883.1:p.Met283Thr
NP_001605.1:p.Met283Thr
NC_000017.10:g.79478089A>G
NR_037688.3:n.920T>C

Protein change:

M283T

Links:

dbSNP: rs2143775617

NCBI 1000 Genomes Browser:

rs2143775617

Molecular consequence:

NM_001199954.3:c.848T>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001614.5:c.848T>C - missense variant - [Sequence Ontology: SO:0001583]
NR_037688.3:n.920T>C - non-coding transcript variant - [Sequence Ontology: SO:0001619]

Observations:

Condition(s)

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

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV002318519	3billion	criteria provided, single submitter (ACMG Guidelines, 2015)	Likely pathogenic (Mar 22, 2022)	germline	clinical testing	PubMed (3) [See all records that cite these PMIDs] 29986705, 30622556, 25741868
SCV003844171	King Laboratory, University of Washington	criteria provided, single submitter (Li et al. (Genet Med. 2022))	Likely pathogenic (Feb 28, 2023)	maternal	research	PubMed (2) [See all records that cite these PMIDs] 36633841, 35802133

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV002318519

3billion

criteria provided, single submitter

(ACMG Guidelines, 2015)

Likely pathogenic
(Mar 22, 2022)

germline

clinical testing

PubMed (3)
[See all records that cite these PMIDs]

SCV003844171

King Laboratory, University of Washington

criteria provided, single submitter

(Li et al. (Genet Med. 2022))

Likely pathogenic
(Feb 28, 2023)

maternal

research

PubMed (2)
[See all records that cite these PMIDs]

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	yes	1	not provided	not provided	1	not provided	clinical testing
not provided	maternal	yes	not provided	not provided	not provided	not provided	not provided	research

Citations

PubMed

Comprehensive genomic diagnosis of non-syndromic and syndromic hereditary hearing loss in Spanish patients.

Cabanillas R, Diñeiro M, Cifuentes GA, Castillo D, Pruneda PC, Álvarez R, Sánchez-Durán N, Capín R, Plasencia A, Viejo-Díaz M, García-González N, Hernando I, Llorente JL, Repáraz-Andrade A, Torreira-Banzas C, Rosell J, Govea N, Gómez-Martínez JR, Núñez-Batalla F, Garrote JA, Mazón-Gutiérrez Á, Costales M, et al.

BMC Med Genomics. 2018 Jul 9;11(1):58. doi: 10.1186/s12920-018-0375-5.

PubMed [citation]

PMID:: 29986705
PMCID:: PMC6038346

Genomic Studies in a Large Cohort of Hearing Impaired Italian Patients Revealed Several New Alleles, a Rare Case of Uniparental Disomy (UPD) and the Importance to Search for Copy Number Variations.

Morgan A, Lenarduzzi S, Cappellani S, Pecile V, Morgutti M, Orzan E, Ghiselli S, Ambrosetti U, Brumat M, Gajendrarao P, La Bianca M, Faletra F, Grosso E, Sirchia F, Sensi A, Graziano C, Seri M, Gasparini P, Girotto G.

Front Genet. 2018;9:681. doi: 10.3389/fgene.2018.00681.

PubMed [citation]

PMID:: 30622556
PMCID:: PMC6309105

See all PubMed Citations (5)

Details of each submission

From 3billion, SCV002318519.1

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

Description

A different missense change at the same codon has been reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000546156, PMID:30622556). In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.916>=0.6, 3CNET: 0.975>=0.75). Missense changes are a common disease-causing mechanism. It is not observed in the gnomAD v2.1.1 dataset. Same nucleotide change resulting in same amino acid change has been previously reported to be associated with ACTG1 related disorder (PMID: 29986705). Therefore, this variant is classified as likely pathogenic according to the recommendation of ACMG/AMP guideline.

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

From King Laboratory, University of Washington, SCV003844171.1

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

Description

This variant was found in heterozygosity in a patient and their mother, both with bilateral sensorineural hearing loss of onset <18 years, in a study of pediatric hearing loss conducted by the King Laboratory (Carlson RJ et al. JAMA-OtoHNS 2023). This patient’s mother has a similar hearing loss, and the family has no other history of hearing loss. This variant is a missense at a completely conserved site and is predicted to be damaging by multiple in-silico tools. As of January 2023, this variant has been reported to ClinVar as likely pathogenic and is not found on gnomAD. Based on consistently predicted functional effect, co-segregation with the phenotype in the family, and goodness of fit of genotype to phenotype, we conclude that this variant is likely pathogenic.

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

Last Updated: Dec 24, 2023

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