NM_001614.5(ACTG1):c.773C>T (p.Pro258Leu) AND Baraitser-winter syndrome 2

Germline classification:: Likely pathogenic (1 submission)
Last evaluated:: Jul 7, 2023
Review status:: 1 star out of maximum of 4 stars
criteria provided, single submitter

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:: RCV003994118.1

Allele description [Variation Report for NM_001614.5(ACTG1):c.773C>T (p.Pro258Leu)]

NM_001614.5(ACTG1):c.773C>T (p.Pro258Leu)

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.773C>T (p.Pro258Leu)

HGVS:

NC_000017.11:g.81511217G>A
NG_011433.1:g.6585C>T
NM_001199954.3:c.773C>T
NM_001614.5:c.773C>TMANE SELECT
NP_001186883.1:p.Pro258Leu
NP_001605.1:p.Pro258Leu
NC_000017.10:g.79478243G>A
NM_001614.3:c.773C>T
NR_037688.3:n.845C>T

Protein change:

P258L

Links:

dbSNP: rs11549191

NCBI 1000 Genomes Browser:

rs11549191

Molecular consequence:

NM_001199954.3:c.773C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001614.5:c.773C>T - missense variant - [Sequence Ontology: SO:0001583]
NR_037688.3:n.845C>T - non-coding transcript variant - [Sequence Ontology: SO:0001619]

Condition(s)

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

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HPSE heparanase [Homo sapiens]
Gene ID:10855

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV004812487	Molecular Genetics, Royal Melbourne Hospital See additional submitters Shariant Australia, Australian Genomics	criteria provided, single submitter (ACMG Guidelines, 2015)	Likely pathogenic (Jul 7, 2023)	germline	clinical testing	PubMed (4) [See all records that cite these PMIDs] 28000701, 31116477, 34448047, 25741868

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV004812487

Molecular Genetics, Royal Melbourne Hospital

See additional submitters

criteria provided, single submitter

(ACMG Guidelines, 2015)

Likely pathogenic
(Jul 7, 2023)

germline

clinical testing

PubMed (4)
[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	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

The diagnostic yield of whole-exome sequencing targeting a gene panel for hearing impairment in The Netherlands.

Zazo Seco C, Wesdorp M, Feenstra I, Pfundt R, Hehir-Kwa JY, Lelieveld SH, Castelein S, Gilissen C, de Wijs IJ, Admiraal RJ, Pennings RJ, Kunst HP, van de Kamp JM, Tamminga S, Houweling AC, Plomp AS, Maas SM, de Koning Gans PA, Kant SG, de Geus CM, Frints SG, Vanhoutte EK, et al.

Eur J Hum Genet. 2017 Feb;25(3):308-314. doi: 10.1038/ejhg.2016.182. Epub 2016 Dec 21.

PubMed [citation]

PMID:: 28000701
PMCID:: PMC5315517

MetaDome: Pathogenicity analysis of genetic variants through aggregation of homologous human protein domains.

Wiel L, Baakman C, Gilissen D, Veltman JA, Vriend G, Gilissen C.

Hum Mutat. 2019 Aug;40(8):1030-1038. doi: 10.1002/humu.23798. Epub 2019 Jun 18.

PubMed [citation]

PMID:: 31116477
PMCID:: PMC6772141

See all PubMed Citations (4)

Details of each submission

From Molecular Genetics, Royal Melbourne Hospital, SCV004812487.1

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

Description

This sequence change in ACTG1 is predicted to replace proline with leucine at codon 258, p.(Pro258Leu). The proline residue is highly conserved (100 vertebrates, UCSC), and is located in a helical region, amino acids 245-300, that is highly intolerant to missense variation (PMID: 31116477). There is a moderate physicochemical difference between proline and leucine. This variant is absent from the population database gnomAD v2.1 and v3.1. This variant has been identified as a de novo occurrence with unconfirmed parental relationships in two individuals with syndromic deafness, including neurodevelopmental and ocular features (PMID: 28000701, 34448047). Computational evidence predicts a deleterious effect for the missense substitution (REVEL = 0.895). Based on the classification scheme RMH Modified ACMG/AMP Guidelines v1.6.1, this variant is classified as LIKELY PATHOGENIC. Following criteria are met: PM6_Strong, PM1, PM2_Supporting, PP3.

#	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: Oct 20, 2024

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