NM_006306.4(SMC1A):c.1756C>T (p.Arg586Trp) AND Congenital muscular hypertrophy-cerebral syndrome

Germline classification:: Likely pathogenic (1 submission)
Last evaluated:: Mar 22, 2022
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:: RCV002052134.1

Allele description [Variation Report for NM_006306.4(SMC1A):c.1756C>T (p.Arg586Trp)]

NM_006306.4(SMC1A):c.1756C>T (p.Arg586Trp)

Gene:

SMC1A:structural maintenance of chromosomes 1A [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

Xp11.22

Genomic location:

Preferred name:

NM_006306.4(SMC1A):c.1756C>T (p.Arg586Trp)

HGVS:

NC_000023.11:g.53405648G>A
NG_006988.2:g.22023C>T
NM_001281463.1:c.1690C>T
NM_006306.4:c.1756C>TMANE SELECT
NP_001268392.1:p.Arg564Trp
NP_006297.2:p.Arg586Trp
LRG_773t1:c.1690C>T
LRG_773:g.22023C>T
LRG_773p1:p.Arg564Trp
NC_000023.10:g.53432580G>A
NM_006306.2:c.1756C>T

Protein change:

R564W

Links:

dbSNP: rs2146599836

NCBI 1000 Genomes Browser:

rs2146599836

Molecular consequence:

NM_001281463.1:c.1690C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_006306.4:c.1756C>T - missense variant - [Sequence Ontology: SO:0001583]

Observations:

Condition(s)

Name:: Congenital muscular hypertrophy-cerebral syndrome (CDLS2)
Synonyms:: Cornelia de Lange syndrome 2
Identifiers:: MONDO: MONDO:0010370; MedGen: C1802395; Orphanet: 199; OMIM: 300590

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV002318616	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] 25125236, 28548707, 25741868

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV002318616

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]

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

Citations

PubMed

Genetic heterogeneity in Cornelia de Lange syndrome (CdLS) and CdLS-like phenotypes with observed and predicted levels of mosaicism.

Ansari M, Poke G, Ferry Q, Williamson K, Aldridge R, Meynert AM, Bengani H, Chan CY, Kayserili H, Avci S, Hennekam RC, Lampe AK, Redeker E, Homfray T, Ross A, Falkenberg Smeland M, Mansour S, Parker MJ, Cook JA, Splitt M, Fisher RB, Fryer A, et al.

J Med Genet. 2014 Oct;51(10):659-68. doi: 10.1136/jmedgenet-2014-102573. Epub 2014 Aug 14.

PubMed [citation]

PMID:: 25125236
PMCID:: PMC4173748

Phenotypes and genotypes in individuals with SMC1A variants.

Huisman S, Mulder PA, Redeker E, Bader I, Bisgaard AM, Brooks A, Cereda A, Cinca C, Clark D, Cormier-Daire V, Deardorff MA, Diderich K, Elting M, van Essen A, FitzPatrick D, Gervasini C, Gillessen-Kaesbach G, Girisha KM, Hilhorst-Hofstee Y, Hopman S, Horn D, Isrie M, et al.

Am J Med Genet A. 2017 Aug;173(8):2108-2125. doi: 10.1002/ajmg.a.38279. Epub 2017 May 26.

PubMed [citation]

PMID:: 28548707

See all PubMed Citations (3)

Details of each submission

From 3billion, SCV002318616.1

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

Description

Different pathogenic/likely pathogenic amino acid change has been reported with supporting evidence at the same codon (PMID:25125236). In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.748>=0.6). A missense variant is a common mechanism . It is not observed in the gnomAD v2.1.1 dataset. 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

Last Updated: Dec 24, 2023

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