ClinVar Miner

Submissions for variant NM_004281.4(BAG3):c.625C>T (p.Pro209Ser)

dbSNP: rs1589630141
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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Labcorp Genetics (formerly Invitae), Labcorp RCV000813879 SCV000954260 pathogenic Myofibrillar myopathy 6; Dilated cardiomyopathy 1HH 2024-07-08 criteria provided, single submitter clinical testing This sequence change replaces proline, which is neutral and non-polar, with serine, which is neutral and polar, at codon 209 of the BAG3 protein (p.Pro209Ser). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with Charcot-Marie-Tooth disease (PMID: 27164712, 28754666). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 657299). 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) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on BAG3 protein function. Experimental studies have shown that this missense change affects BAG3 function (PMID: 30559338). For these reasons, this variant has been classified as Pathogenic.
Kariminejad - Najmabadi Pathology & Genetics Center RCV001836898 SCV001167089 likely pathogenic Abnormality of the musculature 2021-07-10 criteria provided, single submitter clinical testing
Mayo Clinic Laboratories, Mayo Clinic RCV001507780 SCV001713543 pathogenic not provided 2019-10-14 criteria provided, single submitter clinical testing PS3, PS4_moderate, PM2, PM5, PP1
Revvity Omics, Revvity RCV001507780 SCV002023426 pathogenic not provided 2023-08-03 criteria provided, single submitter clinical testing
PreventionGenetics, part of Exact Sciences RCV003392618 SCV004110997 pathogenic BAG3-related disorder 2023-04-10 criteria provided, single submitter clinical testing The BAG3 c.625C>T variant is predicted to result in the amino acid substitution p.Pro209Ser. This variant was reported in multiple individuals with axonal neuropathy/Charcot-Marie-Tooth disease (Table 1, Wang et al 2016. PubMed ID: 27164712; Shy et al 2017. PubMed ID: 28754666; Fu J et al 2019. PubMed ID: 31853710; Taghizadeh et al 2020. PubMed ID: 32657593). Functional studies suggest that substitutions affecting p.Pro209 amino residue (p.Pro209Ser, p.Pro209Leu and p.Pro209Gln) disrupt BAG3 protein function (Adriaenssens. 2020. PubMed ID: 32472079; Meister-Broekema et al 2018. PubMed ID: 30559338). This variant has not been reported in a large population database (http://gnomad.broadinstitute.org), indicating this variant is rare. 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.

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