Submissions for variant NM_012073.5(CCT5):c.440A>G (p.His147Arg)

gnomAD frequency: 0.00040  dbSNP: rs118203986

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV000001390	SCV001216507	uncertain significance	Hereditary sensory and autonomic neuropathy with spastic paraplegia	2024-01-19	criteria provided, single submitter	clinical testing	This sequence change replaces histidine, which is basic and polar, with arginine, which is basic and polar, at codon 147 of the CCT5 protein (p.His147Arg). This variant is present in population databases (rs118203986, gnomAD 0.06%), and has an allele count higher than expected for a pathogenic variant. This missense change has been observed in individual(s) with autosomal recessive mutilating sensory neuropathy with spastic paraplegia (PMID: 16399879). ClinVar contains an entry for this variant (Variation ID: 1327). 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 not expected to disrupt CCT5 protein function with a negative predictive value of 80%. Experimental studies are conflicting or provide insufficient evidence to determine the effect of this variant on CCT5 function (PMID: 25124038, 25345891, 28623285, 29552646). 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.
Illumina Laboratory Services, Illumina	RCV000001390	SCV001318129	uncertain significance	Hereditary sensory and autonomic neuropathy with spastic paraplegia	2017-04-27	criteria provided, single submitter	clinical testing	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.
PreventionGenetics, part of Exact Sciences	RCV003952334	SCV004774907	uncertain significance	CCT5-related disorder	2024-01-04	criteria provided, single submitter	clinical testing	The CCT5 c.440A>G variant is predicted to result in the amino acid substitution p.His147Arg. This variant has been reported in the homozygous state in multiple family members with neuropathy and spastic paraplegia (Figure 1, Bouhouche et al. 2006. PubMed ID: 16399879). This variant is reported in 0.056% of alleles in individuals of Latino descent in gnomAD. The results of in vitro experimental studies of this variant are inconclusive (Sergeeva et al. 2014. PubMed ID: 25124038; Min et al. 2014. PubMed ID: 25345891; Pereira et al. 2017. PubMed ID: 28623285; Spigolon et al. 2017. PubMed ID: 29552646). Although we suspect that this variant may be pathogenic, at this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.
OMIM	RCV000001390	SCV000021540	pathogenic	Hereditary sensory and autonomic neuropathy with spastic paraplegia	2006-05-01	no assertion criteria provided	literature only
GeneDx	RCV000434241	SCV000521259	likely pathogenic	not provided	2016-10-06	flagged submission	clinical testing	The H147R variant in the CCT5 gene has been reported previously in the homozygous state in four brothers with mutilating sensory neuropathy and spastic paraplegia (Bouhouche et al., 2006). The H147R variant was not observed in approximately 6500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. The H147R variant is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties. This substitution occurs at a position that is not conserved and in silico analysis is inconsistent in its predictions as to whether or not the variant is damaging to the protein structure/function. Therefore, we interpret H147R as a likely pathogenic variant,