Submissions for variant NM_006306.4(SMC1A):c.1994G>A (p.Arg665His)

Total submissions: 3

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	RCV002470417	SCV002767831	likely benign	Congenital muscular hypertrophy-cerebral syndrome	2021-05-06	criteria provided, single submitter	clinical testing	Based on the classification scheme VCGS_Germline_v1.3.3, this variant is classified as Likely benign. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with Cornelia de Lange syndrome 2 (MIM#300590) and epileptic encephalopathy, early infantile, 85, with or without midline brain defects. Dominant negative is also a suggested mechanism of disease (PMID: 17273969, 19701948). (I) 0110 - This gene is associated with X-linked dominant disease. This gene is known to escape X-inactivation (PMID: 30871455). (I) 0200 - Variant is predicted to result in a missense amino acid change from arginine to histidine. (I) 0253 - This variant is hemizygous. (I) 0301 - Variant is absent from gnomAD (both v2 and v3). (SP) 0501 - Missense variant consistently predicted to be damaging by multiple in silico tools or highly conserved with a major amino acid change. (SP) 0603 - Missense variant in a region that is highly intolerant to missense variation (high constraint region in DECIPHER). (SP) 0705 - No comparable missense variants have previous evidence for pathogenicity. (I) 0809 - Previous evidence of pathogenicity for this variant is inconclusive. This variant has been reported in a hemizygous patient with Cornelia de Lange syndrome, and described as a VUS (PMID: 30847515). (I) 0905 - No published segregation evidence has been identified for this variant. (I) 1007 - No published functional evidence has been identified for this variant. (I) 1205 - This variant has been shown to be maternally inherited (LABID). (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign
Ambry Genetics	RCV004965883	SCV005509969	likely pathogenic	Inborn genetic diseases	2024-10-30	criteria provided, single submitter	clinical testing	The c.1994G>A (p.R665H) alteration is located in exon 12 (coding exon 12) of the SMC1A gene. This alteration results from a G to A substitution at nucleotide position 1994, causing the arginine (R) at amino acid position 665 to be replaced by a histidine (H). for SMC1A-related Cornelia de Lange syndrome; however, its clinical significance for SMC1A-related developmental and epileptic encephalopathy is uncertain. This variant was not reported in population-based cohorts in the Genome Aggregation Database (gnomAD). This variant was reported as hemizygous in an individual with features consistent with Cornelia de Lange syndrome, but clinical details were limited (French, 2019). This amino acid position is highly conserved in available vertebrate species. This missense alteration is located in a region that has a low rate of benign missense variation (Lek, 2016; Firth, 2009). This alteration is predicted to be deleterious by in silico analysis. Based on the available evidence, this alteration is classified as likely pathogenic.
Labcorp Genetics (formerly Invitae), Labcorp	RCV002470417	SCV005712831	uncertain significance	Congenital muscular hypertrophy-cerebral syndrome	2024-06-13	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 665 of the SMC1A protein (p.Arg665His). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with SMC1A-related conditions. ClinVar contains an entry for this variant (Variation ID: 1806133). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt SMC1A protein function with a positive predictive value of 80%. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.