rs797045993

Variant names:

• chrX-53403617-C-T
• rs797045993
• NM_006306.4:c.2369G>A

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PM1 PM2 PP2 PP3 PP5_Very_Strong

The NM_006306.4(SMC1A):​c.2369G>A​(p.Arg790Gln) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★).

• Frequency: Genomes: not found (cov: 22)
• Consequence: SMC1A NM_006306.4 missense
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:3
• Conservation: PhyloP100: 5.83

Genes affected

SMC1A (HGNC:11111): (structural maintenance of chromosomes 1A) Proper cohesion of sister chromatids is a prerequisite for the correct segregation of chromosomes during cell division. The cohesin multiprotein complex is required for sister chromatid cohesion. This complex is composed partly of two structural maintenance of chromosomes (SMC) proteins, SMC3 and either SMC1B or the protein encoded by this gene. Most of the cohesin complexes dissociate from the chromosomes before mitosis, although those complexes at the kinetochore remain. Therefore, the encoded protein is thought to be an important part of functional kinetochores. In addition, this protein interacts with BRCA1 and is phosphorylated by ATM, indicating a potential role for this protein in DNA repair. This gene, which belongs to the SMC gene family, is located in an area of the X-chromosome that escapes X inactivation. Mutations in this gene result in Cornelia de Lange syndrome. Alternative splicing results in multiple transcript variants encoding different isoforms. [provided by RefSeq, Jul 2013]

ACMG classification

Verdict is Pathogenic. Variant got 14 ACMG points.

• PM1: In a coiled_coil_region (size 275) in uniprot entity SMC1A_HUMAN there are 4 pathogenic changes around while only 0 benign (100%) in NM_006306.4
• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant in the SMC1A gene, where missense mutations are typically associated with disease (based on misZ statistic). The gene has 68 curated pathogenic missense variants (we use a threshold of 10). The gene has 31 curated benign missense variants. Gene score misZ: 6.4479 (above the threshold of 3.09). GenCC associations: The gene is linked to Cornelia de Lange syndrome, X-linked complex neurodevelopmental disorder, atypical Rett syndrome, Cornelia de Lange syndrome 2, developmental and epileptic encephalopathy, 85, with or without midline brain defects.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.796
• PP5: Variant X-53403617-C-T is Pathogenic according to our data. Variant chrX-53403617-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 212267.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-53403617-C-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SMC1A	NM_006306.4	c.2369G>A	p.Arg790Gln	missense_variant	Exon 15 of 25	ENST00000322213.9	NP_006297.2
SMC1A	NM_001281463.1	c.2303G>A	p.Arg768Gln	missense_variant	Exon 16 of 26		NP_001268392.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SMC1A	ENST00000322213.9	c.2369G>A	p.Arg790Gln	missense_variant	Exon 15 of 25	1	NM_006306.4	ENSP00000323421.3
SMC1A	ENST00000375340.10	c.2303G>A	p.Arg768Gln	missense_variant	Exon 16 of 26	1		ENSP00000364489.7
SMC1A	ENST00000675504.1	c.2303G>A	p.Arg768Gln	missense_variant	Exon 15 of 25			ENSP00000502524.1
SMC1A	ENST00000674590.1	c.1601G>A	p.Arg534Gln	missense_variant	Exon 13 of 23			ENSP00000502626.1

Frequencies

GnomAD3 genomes Cov.: 22

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 22

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Congenital muscular hypertrophy-cerebral syndrome Pathogenic:2

May 30, 2017

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

For these reasons, this variant has been classified as Pathogenic. This sequence change replaces arginine with glutamine at codon 790 of the SMC1A protein (p.Arg790Gln). The arginine residue is highly conserved and there is a small physicochemical difference between arginine and glutamine. This variant is not present in population databases (rs797045993, ExAC no frequency). This variant has been reported as de novo in two individuals affected with Cornelia de Lange syndrome (PMID: 17273969, Invitae). ClinVar contains an entry for this variant (Variation ID: 212267). 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"). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may alter RNA splicing, but this prediction has not been confirmed by published transcriptional studies. -

Nov 26, 2014

Genetic Services Laboratory, University of Chicago

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

SMC1A-related disorder Pathogenic:1

Mar 11, 2024

PreventionGenetics, part of Exact Sciences

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

The SMC1A c.2369G>A variant is predicted to result in the amino acid substitution p.Arg790Gln. This variant was reported in individuals with Cornelia de Lange syndrome (Deardorff et al. 2007. PubMed ID: 17273969; Table 3, Pablo et al. 2021. PubMed ID: 34717699) and in a cohort of individuals with autism spectrum disorder (ASD, Supplementary Data 1, Zhou et al. 2022. PubMed ID: 35982159). This variant has not been reported in a large population database (http://gnomad.broadinstitute.org), indicating this variant is rare. This variant is interpreted as pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.98
BayesDel_addAF	Pathogenic	0.35	D
BayesDel_noAF	Pathogenic	0.26
CADD	Pathogenic	28
DANN	Pathogenic	1.0
DEOGEN2	Uncertain	0.55	D;T
FATHMM_MKL	Uncertain	0.89	D
LIST_S2	Pathogenic	0.98	D;D
M_CAP	Pathogenic	0.46	D
MetaRNN	Pathogenic	0.80	D;D
MetaSVM	Uncertain	0.54	D
MutationAssessor	Uncertain	2.8	M;.
PrimateAI	Uncertain	0.76	T
PROVEAN	Uncertain	-3.6	D;.
REVEL	Pathogenic	0.81
Sift	Pathogenic	0.0	D;.
Sift4G	Pathogenic	0.0	D;D
Polyphen		1.0	D;.
Vest4		0.78
MutPred		0.83		Loss of MoRF binding (P = 0.0735);.;
MVP		0.98
MPC		3.0
ClinPred		1.0	D
GERP RS		4.6
RBP_binding_hub_radar		0.92
RBP_regulation_power_radar		2.6
Varity_R		0.90
gMVP		0.85

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs797045993; hg19: chrX-53430549; COSMIC: COSV59127614; COSMIC: COSV59127614;