NM_006306.4(SMC1A):c.3254A>G (p.Tyr1085Cys) AND Congenital muscular hypertrophy-cerebral syndrome

Germline classification:: Pathogenic/Likely pathogenic (2 submissions)
Last evaluated:: Apr 7, 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:: RCV000147566.13

Allele description [Variation Report for NM_006306.4(SMC1A):c.3254A>G (p.Tyr1085Cys)]

NM_006306.4(SMC1A):c.3254A>G (p.Tyr1085Cys)

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.3254A>G (p.Tyr1085Cys)

HGVS:

NC_000023.11:g.53382537T>C
NG_006988.2:g.45134A>G
NM_001281463.1:c.3188A>G
NM_006306.4:c.3254A>GMANE SELECT
NP_001268392.1:p.Tyr1063Cys
NP_006297.2:p.Tyr1085Cys
NP_006297.2:p.Tyr1085Cys
LRG_773t1:c.3188A>G
LRG_773t2:c.3254A>G
LRG_773:g.45134A>G
LRG_773p1:p.Tyr1063Cys
LRG_773p2:p.Tyr1085Cys
NC_000023.10:g.53409458T>C
NM_006306.2:c.3254A>G
NM_006306.3:c.3254A>G
Q14683:p.Tyr1085Cys

Protein change:

Y1063C

Links:

UniProtKB: Q14683#VAR_062801; dbSNP: rs587784418

NCBI 1000 Genomes Browser:

rs587784418

Molecular consequence:

NM_001281463.1:c.3188A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_006306.4:c.3254A>G - missense variant - [Sequence Ontology: SO:0001583]

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
SCV000195014	Genetic Services Laboratory, University of Chicago	criteria provided, single submitter (ACMG Guidelines, 2007)	Pathogenic (Feb 8, 2013)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV000637996	Invitae	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Likely pathogenic (Apr 7, 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

SCV000195014

Genetic Services Laboratory, University of Chicago

criteria provided, single submitter

(ACMG Guidelines, 2007)

Pathogenic
(Feb 8, 2013)

germline

clinical testing

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

SCV000637996

Invitae

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Likely pathogenic
(Apr 7, 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	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing
not provided	germline	yes	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

ACMG recommendations for standards for interpretation and reporting of sequence variations: Revisions 2007.

Richards CS, Bale S, Bellissimo DB, Das S, Grody WW, Hegde MR, Lyon E, Ward BE; Molecular Subcommittee of the ACMG Laboratory Quality Assurance Committee..

Genet Med. 2008 Apr;10(4):294-300. doi: 10.1097/GIM.0b013e31816b5cae.

PubMed [citation]

PMID:: 18414213

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

Details of each submission

From Genetic Services Laboratory, University of Chicago, SCV000195014.1

#	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	germline	yes	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Invitae, SCV000637996.5

#	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 tyrosine with cysteine at codon 1085 of the SMC1A protein (p.Tyr1085Cys). The tyrosine residue is moderately conserved and there is a large physicochemical difference between tyrosine and cysteine. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site, but this prediction has not been confirmed by published transcriptional studies. Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). Family studies have shown that this variant co-segregates with disease in a family with features consistent with Cornelia de Lange syndrome (Invitae). This variant has been reported to be de novo in an individual affected with Cornelia de Lange syndrome. ClinVar contains an entry for this variant (Variation ID: 159956). This variant is not present in population databases (ExAC no frequency).

#	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

Last Updated: Feb 28, 2024

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